Kras g12c inhibitors

Abstract

The present invention relates to compounds of Formula (II) that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

Description

KRAS G12C INHIBITORSFIELD OF THE INVENTION

[0001] The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.BACKGROUND OF THE INVENTION

[0002] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRas”) is a small GTPase and a member of the Ras family of oncogenes. KRas serves a molecular switch cycling between inactive (GDP-bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cellular proliferation (e.g., see Alamgeer et ah, (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignancy was observed over thirty years ago (e.g., see Santos et ah, (1984) Science 223:661-664). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25 -30% of lung adenocarcinomas (e.g., see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928-942 doi: 10.l038 / nrd428). Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma, with a G12C transversion being the most common activating mutation (e.g., see Dogan et ah, (2012) Clin Cancer Res. 18(22):6169-6177, published online 2012 Sep 26. doi: 10.1 158 / 1078-0432.CCR- 1 1-3265).

[0004] The well-known role of KRAs in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractable target of the pharmaceutical industry for cancer therapy. Notwithstanding thirty years of large scale discovery efforts to develop inhibitors of KRas for treating cancer, no KRas inhibitor hasdemonstrated sufficient safety and / or efficacy to obtain regulatory approval (e.g., seeMcCormick (2015) Clin Cancer Res. 21 (8): 1797- 1801 ).

[0005] Despite many failed efforts to target KRas, compounds that inhibit KRas activity are still highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., see Sun et ah, (2012) Agnew Chem Int Ed Engl.51 (25):6140-6143 doi: l0.l002 / anie20l20l358) as well target KRas G12C (e.g., see Ostrem et al., (2013) Nature 503:548-551). Clearly there remains a continued interest and effort to develop inhibitors of KRas, particularly inhibitors of activating KRas mutants, including KRas G12C.

[0006] Thus, there is a need to develop new KRas G12C inhibitors that demonstrate sufficient efficacy, stability and / or safety for treating KRas Gl2C-mediated cancer. The compounds and compositions of the present invention advantageously overcome one or more of the previous shortcomings by providing selective KRas G12C inhibitors.SUMMARY OF THE INVENTION

[0007] In one aspect of the invention, compounds are provided that inhibit KRas G12C activity. In certain embodiments, the compounds are represented by formula (I):Formula (I)

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0010] X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R8;

[0011] Y is a bond, O, S or NR5;

[0013] R2is hydrogen, alkyl, hydroxyalkyl, dihydroxy alkyl, alkylaminylalkyl,dialkylaminylalkyl, -Z-NR5R10, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, orheteroarylalkyl, wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R9;

[0014] Z is Cl - C4 alkylene;

[0015] each R3is independently Cl - C3 alkyl, oxo, or haloalkyl;

[0016] L is a bond, -C(O)-, or Cl - C3 alkylene;

[0017] R4is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R6or R7;

[0018] each R5is independently hydrogen or Cl - C3 alkyl;

[0019] R6is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R7;

[0020] each R7is independently halogen, hydroxyl, Cl - C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;

[0021] R8is oxo, Cl - C3 alkyl, C2 - C4 alkynyl, heteroalkyl, cyano, -C(0)OR5, -C(0)N(R5)2, - N(R5)2, wherein the Cl - C3 alkyl may be optionally substituted with cyano, halogen, -OR5, - N(R5)2, or heteroaryl

[0022] each R9is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen,Cl - C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the Cl - C6 alkyl may be optionally substituted with cycloalkyl;

[0023] each R10is independently hydrogen, acyl, Cl - C3 alkyl, heteroalkyl or hydroxyalkyl;

[0024] RAis absent, hydrogen, or Cl - C3 alkyl;

[0025] each RBis independently hydrogen, Cl - C3 alkyl, alkylaminylalkyl, dialkylaminylalkyl or heterocyclylalkyl;

[0026] m is zero or an integer between 1 and 2;

[0027] p is one or two; and wherein,

[0028] when== is a triple bond then RAis absent, RBis present and p equals one,

[0029] or when - .— is a double bond then RAis present, RBis present and p equals two, orRa, RBand the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl optionally substituted with one or more R7.

[0030] Also included are compounds of Formula I having the Formula I-A:Formula I-A

[0031] wherein R1, R3, R4, R3, R10, L and m are as defined for Formula I, R1 1ishydrogen, Cl - C3 alkyl or hydroxyalkyl, and the piperazinyl ring is optionally substituted with R8wherein R8is as defined for Formula I.

[0032] Also included are compounds of Formula I having the Formula I-B:Formula I-B

[0033] where R1, R3, R4, L and m are as defined for Formula I, R2is heterocyclylalkyl optionally substituted with one or more R9where R9is as defined for Formula I, and the piperazinyl ring is optionally substituted with R8, where R8is as defined for Formula I.

[0034] In certain embodiments, the compounds are represented by Formula (II):Formula (II)

[0035] or a pharmaceutically acceptable salt thereof:

[0036] wherein:

[0037] X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R8;

[0038] Y is a bond, O, S or NR5;

[0039] R1is -C(0)C(Ra) ^^~C(RB)Por -S02C(RA) ^^= c(RB)p;

[0040] R2is hydrogen, alkyl, hydroxyalkyl, dihydroxy alkyl, alkylaminylalkyl,dialkylaminylalkyl, -Z-NR5R10, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, orheteroarylalkyl, wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R9;

[0041] each Z is Cl - C4 alkylene;

[0042] each R3is independently Cl - C3 alkyl, oxo, haloalkyl, hydroxyl or halogen;

[0043] L is a bond, -C(O)-, or Cl - C3 alkylene;

[0044] R4is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R6, R7or R8;

[0045] each R5is independently hydrogen or Cl - C3 alkyl;

[0046] R6is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R7;

[0047] each R7is independently halogen, hydroxyl, Cl - C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;

[0048] R8is oxo, Cl - C3 alkyl, C2 - C4 alkynyl, heteroalkyl, cyano, -C(0)OR5, -C(0)N(R5)2, - N(R5)2, wherein the Cl - C3 alkyl may be optionally substituted with cyano, halogen, -OR5, - N(R5)2, or heteroaryl;

[0049] each R9is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen,Cl - C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl,alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the Cl - C6 alkyl may be optionally substituted with cycloalkyl;

[0050] each R10is independently hydrogen, acyl, Cl - C3 alkyl, heteroalkyl or hydroxyalkyl;

[0051] R11is haloalkyl;

[0052] RAis absent, hydrogen, deuterium, cyano, halogen, Cl - C-3 alkyl, haloalkyl, heteroalkyl, -C(0)N(R5)2, or hydroxyalkyl;

[0053] each RBis independently hydrogen, deuterium, cyano, Cl - C3 alkyl, hydroxyalkyl, heteroalkyl, Cl - C3 alkoxy, halogen, haloalkyl, -ZNR5Rn, -C(0)N(R5)2, -NHC(0)Cl - C3 alkyl, -CH2NHC(0)Cl - C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and Cl - C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R7;

[0054] or when — is a double bond and p is two, one RBis hydrogen and RAand one RBand the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl substituted with oxo;

[0055] m is zero or an integer between 1 and 2;

[0056] p is one or two; and wherein,

[0057] when - .— is a triple bond then RAis absent, p equals one and RBis hydroxyalkyl,

[0058] or when is a double bond then RAis present, RBis present and p equals two, wherein when RAis hydrogen or Cl - C3 alkyl at least one RBis deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, -ZNR5RU, -C(0)N(R5)2, - NHC(0)C1 - C3 alkyl, -CH2NHC(0)Cl - C3 alkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy or Cl - C3 alkyl; or when each RBis hydrogen, then RAis deuterium, cyano, halogen, haloalkyl, -C(0)N(R5)2, hydroxyalkyl or heteroalkyl.

[0059] Also included are compounds of Formula II having the Formula II-A:Formula II-A

[0060] wherein R1, R3, R4, R5, R10, L and m are as defined for Formula II, R11is hydrogen, Cl - C3 alkyl or hydroxyalkyl, and the piperazinyl ring is optionally substituted with R8wherein R8is as defined for Formula II.

[0061] Also included are compounds of Formula II having the Formula II-B:Formula II-B

[0062] where R1, R3, R4, R8, L and m are as defined for Formula II, R2is heterocyclylalkyl optionally substituted with one or more R9, and the piperazinyl ring is optionally substituted with R8, where R8is as defined for Formula II.

[0063] In another aspect of the invention, pharmaceutical compositions are provided comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0064] In yet another aspect of the invention, methods for inhibiting KRas G12C activity in a in a cell, comprising contacting the cell with a compound of Formula I, Formula I-A, Formula 1- B, Formula II, Formula II-A or Formula II-B. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0065] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula I, Formula I-A, Formula l-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0066] Also provided are methods for treating cancer in a patient comprising administering a therapeutically effective amount of a compound or pharmaceutical composition of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0067] Also provided herein is a method of treating a KRas G12C -associated disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula l-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

[0068] Also provided herein is a compound of Formula I, Formula I-A, Formula 1 -B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein for use in therapy.

[0069] Also provided herein is a compound of Formula I, Formula I-A, Formula l -B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.

[0070] Also provided herein is a compound of Formula I, Formula I-A, Formula l -B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof for use in the inhibition of KRas G12C.

[0071] Also provided herein is a compound of Formula I, Formula I-A, Formula 1-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a KRas G12C- associated disease or disorder.

[0072] Also provided herein is the use of a compound of Formula I, Formula I-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.

[0073] Also provided herein is a use of a compound of Formula I, Formula I-A, Formula 1-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of KRas G12C.

[0074] Also provided herein is the use of a compound of Formula I, Formula I-A, Formula l-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRas Gl2C-associated disease or disorder.

[0075] Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRas Gl2C-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0076] Also provided herein is a process for preparing a compound of Formula I, Formula I-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof.

[0077] Also provided herein is a compound of Formula I, Formula I-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt thereof obtained by a process of preparing the compound as defined herein.DETAILED DESCRIPTION OF THE INVENTION

[0078] The present invention relates to inhibitors of KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C,pharmaceutical compositions comprising a therapeutically effective amount of the compounds and methods of use therefor.DEFINITIONS

[0079] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference.

[0080] As used herein,“KRas G12C” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Glyl2Cys.

[0081] As used herein, a“KRas G12C inhibitor” refers to compounds of the present invention that are represented by formulae (I) as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12C. The KRas G12C inhibitors of the present invention interact with and irreversibly bind to KRas G12C by forming a covalent adduct with the sulfhydryl side chain of the cysteine residue at position 12 resulting in the inhibition of the enzymatic activity of KRas G12C.

[0082] A "KRas G12C-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas Gl2C-associated cancer.

[0083] As used herein, the term“subject,” "individual," or "patient," used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, thesubject has been identified or diagnosed as having a cancer having a KRas G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a KRas G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a tumor(s) that is positive for a KRas G12C mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a KRas G12C gene-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a KRas G12C mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0084] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the patient has KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12C-associated cancer, a patient having one or more symptoms of a KRas G12C-associated cancer, and / or a patient that has an increased risk of developing a KRas Gl2C-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISFI analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.

[0085] The term“regulatory agency” is a country’s agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0086] The term“amino” refers to -NH2;

[0087] The term "acyl" refers to -C(0)CH3.

[0088] The term "alkyl" as employed herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, 1-8 carbon atoms 1-6 carbon atoms, or 1-3 carbon atoms which is optionally substituted with one, two or three substituents. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0089] The term“haloalkyl” refers to an alkyl chain in which one or more hydrogen has been replaced by a halogen. Examples of haloalkyls are trifluoromethyl, difluoromethyl and fluoromethyl.

[0090] The term“haloalkyloxy” refers to -O-haloalkyl.

[0091] An "alkylene," group is an alkyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Exemplary alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.

[0092] The term“alkoxy” refers to -OC1 - C6 alkyl.

[0093] The term "cycloalkyl" as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0094] The term "heteroalkyl" refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from the group consisting of O, S, and N.

[0095] As used herein, the term“hydroxyalkyl” refers to -alkyl-OH.

[0096] The term“dihydroxyalkyl” refers to an alkyl group as defined herein wherein two carbon atoms are each substituted with a hydroxyl group.

[0097] The term“alkylaminyl” refers to -NRx-alkyl. wherein Rxis hydrogen. In one embodiment, Rxis hydrogen.

[0098] The term“dialkylaminyl” refers to -N(Ry)2, wherein each Ryis C l - C3 alkyl.

[0099] The term“alkylaminylalkyl” refers to -alkyl-NRx-alkyl, wherein Rxis hydrogen in one embodiment, Rxis hydrogen.

[0100] The term“dialkylaminylalkyl” refers to -alkyl -N(Ry)2, wherein each Ryis Cl - C4 alkyl, wherein the alkyl of the— alkyl-N(Ry)2may be optionally substituted with hydroxy or hydroxyalkyl.

[0101] An "aryl" group is a C6-Ci4aromatic moiety comprising one to three aromatic rings, which is optionally substituted. As one embodiment, the aryl group is a CV,-Cio aryl group. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.

[0102] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted. An example of an aralkyl group is (Ci- C6)alkyl(C6-Cio)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. An example of a substituted aralkyl is wherein the alkyl group is substituted with hydroxyalkyl.

[0103] A "heterocyclyl" or "heterocyclic" group is a ring structure having from about 3 to about 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S, the remainder of the ring atoms being carbon. The heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system. The heterocyclic group is optionally substituted with R7on carbon or nitrogen at one or more positions, wherein R7is as defined for Formula I. The heterocyclic group is also independently optionally substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl,decahydroquinolinyl, piperidonyl, 4-piperidinonyl, thiomorpholinyl, thiomorpholinyl 1 ,1 dioxide, morpholinyl, oxazepanyl, azabicyclohexanes, azabicycloheptanes and oxaazabiocycloheptanes. Specifically excluded from the scope of this term are compounds having adjacent annular O and / or S atoms.

[0104] The term“heterocyclylalkyl” refers to a heterocyclyl group as defined herein linked to the remaining portion of the molecule via an alkyl linker, wherein the alkyl linker of the heterocyclylalkyl may be optionally substituted with hydroxy or hydroxyalkyl.

[0105] As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 p electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1 ,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1 ,2,3- thiadiazolyl, 1 ,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1,2,5-triazolyl, 1 ,3,4-triazolyl, and xanthenyl.

[0106] A "heteroarylalkyl" group comprises a heteroaryl group covalently linked to an alkyl group, wherein the radical is on the alkyl group, either of which is independently optionally substituted or unsubstituted. Examples of heteroarylalkyl groups include a heteroaryl group having 5, 6, 9, or 10 ring atoms bonded to a C1-C6 alkyl group. Examples ofheteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl,imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl,benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent annular O and / or S atoms.

[0107] As used herein,“an effective amount” of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0108] As used herein, a "therapeutically effective amount" of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0109] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.[001 10] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.COMPOUNDS

[0111] In one aspect of the invention, compounds are provided represented by formula(I):Formula (I)[001 12] or a pharmaceutically acceptable salt thereof, wherein:

[0113] X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R8;

[0114] Y is a bond, O, S or NR5;[001 15] R1is -C(0)C(Ra) C(RB)Por -S02C(RA) C(RB)P;

[0116] R2is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR5R10, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroaryl alkyl, wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroaryl alkyl may be optionally substituted with one or more R9;[001 17] Z is Cl - C4 alkylene;[001 18] each R3is independently Cl - C3 alkyl, oxo, or haloalkyl;[001 19] L is a bond, -C(O)-, or Cl - C3 alkylene;

[0120] R4is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R6or R7;

[0121] each R5is independently hydrogen or C 1 - C3 alkyl;

[0122] R6is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R7;

[0123] each R7is independently halogen, hydroxyl, Cl - C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;

[0124] R8is oxo, Cl - C3 alkyl, C2 - C4 alkynyl, heteroalkyl, cyano, -C(0)OR5, - C(0)N(R5)2, -N(R5)2, wherein the Cl - C3 alkyl may be optionally substituted with cyano, halogen, -OR5, -N(R5)2, or heteroaryl;

[0125] each R9is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, Cl - C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the Cl— C6 alkyl may be optionally substituted with cycloalkyl;

[0126] each R10is independently hydrogen, acyl, Cl - C3 alkyl, heteroalkyl orhydroxyalkyl;

[0127] Rais absent, hydrogen, or Cl - C3 alkyl;

[0128] each RBis independently hydrogen, Cl - C3 alkyl, alkylaminylalkyl,dialkylaminylalkyl or heterocyclylalkyl;

[0100] m is zero or an integer between 1 and 2;

[0101] p is one or two; and wherein,

[0102] when is a triple bond then RAis absent, RBis present and p equals one;

[0103] or when .::is a double bond then RAis present, RBis present and p equals two, orRa, RBand the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl optionally substituted with one or more R7.

[0104] In certain embodiments, R'-X is:

[0105] wherein R1is are defined for Formula I and the piperazinyl ring is optionally substituted with R8, where R8is as defined for Formula I. In certain embodiments, R8is Cl - C3 alkyl wherein the alkyl is optionally substituted with cyano or OR5, or -C(0)N(R5)2wherein each R5is independently hydrogen or Cl - C3 alkyl.

[0106] In particular embodiments, R1is -C(0)C(RA) =^= C(RB)Pwhere RA, RBand p are as defined for Formula I. In one embodiment, R1is -C(0)C(RA) C(RB)P, wherein === is a triple bond and RAis absent, p is one and RBis Cl - C3 alkyl. In one embodiment, R1is -C(0)C(Ra) . = C(Rb)p, wherein - . is a double bond and RAis hydrogen or Cl -C3alkyl, p is two and each RBis independently hydrogen, Cl - C3alkyl, dialkylaminylalkyl or heterocyclylalkyl. In one embodiment, R1is -C(0)C(RA) =C(RB)P, wherein RAis hydrogen or Cl - C3alkyl, p is two, one of said RBis hydrogen, Cl - C3alkyl, dialkylaminylalkyl or heterocyclylalkyl and the other RBis hydrogen or Cl - C3alkyl. In one embodiment, R1is - C(0)CH=CH2.

[0107] In one embodiment, Y is O or NR5and R2is selected from the group consisting of alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, heterocyclyl,heterocyclylalkyl, and heteroaryl. In one embodiment, Y is O and R2is hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, or dialkylaminylalkyl, wherein the alkylaminylalkyl ordialkylaminylalkyl is optionally substituted with one or more R9. In one embodiment, the optionally substituted alkylaminylalkyl or dialkylaminylalkyl is independently selected from methylaminylpropan-2-yl, dimethylaminylethyl, methylethylaminylethyl,dimethylaminylpropanyl, dimethylaminylpropan-2-yl, dimethylaminylbutanyl,dimethylaminylbutan-2-yl, 2-dimethylaminylpropanol, or diethylaminylethyl. In one embodiment, Y is O or NR5and R2is heterocyclyl or heterocyclylalkyl optionally substituted with one or more R9. Nonlimiting examples of one or more R9when R2is heterocyclyl or heterocyclylalkyl include Cl - C3 alkyl, acyl, oxo, cyano, alkoxy, cycloalkyl, cycloalkylmethyl, halogen, and hydroxyl. Nonlimiting examples of R2heterocyclyls optionally substituted with one or more R9include azetidinyl, C1-C3 alkyl-substituted azetidinyl (e.g., methylazetidinyl), halo-substituted azetidinyl (e.g., difluoroazetidinyl), tetrahydropyran, pyrrolidinyl, C1-C3 alkyl- substituted pyrrolidinyl (e.g., methylpyrrolidinyl, dimethylpyrrolidinyl, andisopropylpyrrolidinyl), cycloalkylalkylpyrrolidinyl, hydroxypyrrolindinyl, halo-substituted pyrrolidinyl (e.g., fluoropyrrolidinyl and difluoropyrrolidinyl), methoxyethylpyrrolidinyl, (N- methyl)methoxypyrrolidinyl, piperazinyl, dimethylaminylpyrrolidinyl, morpholinyl,methylmorpholinyl, 1 ,4-oxazepanyl, piperdinyl, C1-C3 alkyl-substituted piperidinyl (e.g., methylpiperidinyl), acylpiperdinyl, cyanopiperdinyl, cycloalkylpiperdinyl, halopiperdinyl (e.g., fluoropiperdinyl), dihalopiperdinyl (e.g., difluoropiperdinyl), alkoxypiperdinyl, pyrrolidonyl, piperidonyl, thiomorpholinyl- 1,1 -dioxide, 3-azabicyclo[3.l .0]hexanyl, oxa-5- azabicyclo[2.2.1]heptan-5-yl, and azabicyclo[2.2.1]heptan-2-yl.

[0108] In one embodiment, Y is O and R2is heteroarylalkyl optionally substituted with one or more R9. In one embodiment, the heteroaryl portion of the heteroarylalkyl is pyridinyl.

[0109] In one embodiment, Y is O and R2is -ZR3R10. In one embodiment, R- is Cl - C3 alkyl and R10is independently selected from acyl, hydroxyalkyl or alkoxy.

[0110] In one embodiment, Y is a bond and R2is hydrogen, heterocyclyl or aryl, wherein said heterocyclyl and aryl are optionally substituted with one or more R9.[01 1 1] In one embodiment, Y is a bond and R2is hydrogen.

[0112] In one embodiment, Y is a bond and R2is heterocyclyl optionally substituted with one or more R9. In one embodiment, Y is a bond and R2is heterocyclyl optionally substituted withmethyl, halogen or dimethylamino. Nonlimiting examples of R2heterocyclyls include azetidinyl, piperidinyl, piperazinyl, morpholinyl, and pyrrolidinyl.

[0113] In one embodiment, Y is a bond and R2is aryl optionally substituted with one or more R9. In one embodiment, the aryl is phenyl substituted with heterocyclylalkyl.

[0114] In certain other embodiments when X is a monocyclic ring, R4is aryl. In oneembodiment, R4is selected from the group consisting of phenyl and naphthyl and is optionally substituted with one or more R6or R7. Examples of R7substituents include halogen, hydroxyl, Cl- C6 alkyl (e.g., Cl - C3 alkyl), cycloalkyl, haloalkyl, Q-haloalkyl, amino, cyano,hydroxyalkyl and alkoxy. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl,trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl and trifluoromethylthio. In one embodiment, the aryl is phenyl substituted with one to three R7groups independently selected from hydroxyl, fluorine and chlorine. In one embodiment, the aryl is phenyl substituted with hydroxyl and Cl - C3 alkyl or two Cl - C3 alkyl. In one embodiment, the aryl is phenyl substituted with Q-haloalkyl and hydroxyl or fluorine.

[0115] In one embodiment, R4is aryl wherein aryl is naphthyl optionally substituted with one or more R7. In one embodiment, the aryl is naphthyl substituted with one or more R7groups independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is naphthyl substituted with one or more R7groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, R4is naphthyl optionally substituted with one or more R7substituents independently selected from hydroxyl, halogen, Cl - C3 alkyl, amino, and haloalkyl. In one embodiment, R4is naphthyl optionally substituted with one to three R7substituents independently selected from difluoromethyl, methyl, hydroxyl, amino, fluoro, and chloro.

[0116] In one embodiment, the aryl is naphthyl optionally substituted with one or more halogen. In one embodiment, the aryl is naphthyl substituted with hydroxyl and trifluoromethyl or Cl - C3 alkyl. In one embodiment, the aryl is naphthyl substituted with hydroxyl.

[0117] In one embodiment, R4is heteroaryl optionally substituted with one or more R7. In one embodiment, R4is heteroaryl optionally substituted with one or more R7independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, alkoxy and amino. In one embodiments, R4is indoyl, indazolyl, quinolinyl, isoquinolinyl, pyridinyl or benzo[d]thiazolyl optionally substituted with one or more R7. In one embodiments, R4is indoyl, indazolyl, quinolinyl, isoquinolinyl, pyridinyl or benzo[d]thiazolyl optionally substituted with one or more R7independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, alkoxy and amino.

[0118] In yet other embodiments, R4is heteroaryl, optionally an indoyl or an indazolyl, each of which may be substituted with one or more R7. In one embodiment, R4is heteroaryl optionally substituted with one or more R7substituents independently selected from the group consisting of halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl and alkoxy. In one embodiment, the R4heteroaryl is indazolyl optionally substituted with one or two R7independently selected from alkoxy, haloalkyl, and C1-C6 alkyl. In other embodiments, the R4heteroaryl is a quinolinyl or isoquinolinyl, each optionally substituted with one or more R7. In oneembodiment, the R4heteroaryl is a quinolinyl or isoquinolinyl, each optionally substituted with one or more R7independently selected from amino, hydroxyl, Cl - C3 alkyl, and hydroxyl. In one embodiment, the R4heteroaryl is a quinolinyl or isoquinolinyl, each optionally substituted with R7selected from hydroxyl and amino. In one embodiment, the R4heteroaryl is a pyridinyl optionally substituted with one or more R7. In one embodiment, the R4heteroaryl is pyridinyl optionally substituted with one or more R7independently selected from Cl - C3 alkyl, halogen and haloalkyl. In other embodiments, the R4heteroaryl is benzo[d]thiazolyl optionally substituted with one or more R7, such as hydroxyl, one or two Cl - C3 alkyl, or hydroxyl and one or two Cl - C3 alkyl. In one embodiment, the R4heteroaryl is indolyl optionally substituted with one or more R7. In one embodiment, the R4heteroaryl is indolyl optionally substituted with one or two R7independently selected from hydroxyl and Cl - C3alkyl.

[0119] In one embodiment, where X is a monocyclic ring, R4is aralkyl. In certain embodiments, the aralkyl is benzyl. In other embodiments, the alkyl of the benzyl group is optionally substituted with hydroxyalkyl.

[0120] In one embodiment, L is a bond.

[0121] In one embodiment, m is one and R3is Cl - C3 alkyl.

[0122] ln one embodiment, m is one and R3is oxo.

[0123] In one embodiment, R8is heteroalkyl, C2-C4 alkynyl or Cl - C3 alkyl optionally substituted with -OR5, cyano or heteroaryl. In one embodiment, R8is methyl, cyanomethyl, methoxymethyl, hydroxymethyl. In one embodiment, R8is methyl. In one embodiment, R8is cyanomethyl. In one embodiment, R8is hydroxymethyl.

[0124] In one embodiment, Formula I includes compounds having the Formula I-A:

[0125] wherein R1, R3, R4, R5, R10, L and m are as defined for Formula I, R1 1is hydrogen, methyl or hydroxyalkyl, and the piperidinyl ring is optionally substituted with R8wherein R8is as defined for Formula I. In one embodiment, L is a bond. In one embodiment, R4is aryl or heteroaryl, each of which is optionally substituted with one or more R6or R7. In one embodiment, R4is aryl or heteroaryl, each of which is optionally substituted with one or more R7. In one embodiment, each R7is independently selected from hydroxyl, amino, halogen, C l - C3 alkyl, haloalkyl, Q-haloalkyl, cycloalkyl and alkoxy. In one embodiment, R5and R10areeach Cl - C3 alkyl. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl,trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl and trifluoromethylthio. In one embodiment, the aryl is phenyl substituted with one to three R7groups independently selected from hydroxyl, fluorine and chlorine. In one embodiment, the aryl is phenyl substituted with hydroxyl and Cl - C3 alkyl or two Cl - C3 alkyl. In one embodiment, the aryl is phenyl substituted with Q-haloalkyl and hydroxyl or fluorine. In one embodiment, the aryl is naphthyl substituted with one or more R7groups independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is naphthyl substituted with one or more R7groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, R4is naphthyl optionally substituted with one or more R7substituents independently selected from hydroxyl, halogen, Cl - C3 alkyl, amino, and haloalkyl. In one embodiment, R4is naphthyl optionally substituted with one to three R7substituents independently selected fromdifluoromethyl, methyl, hydroxyl, amino, fluoro, and chloro. In one embodiment, the aryl is naphthyl optionally substituted with one or more halogen. In one embodiment, the aryl is naphthyl substituted with hydroxyl and trifluoromethyl or Cl - C3alkyl. In one embodiment, the aryl is naphthyl substituted with hydroxyl. In one embodiment, R4is heteroaryl, wherein the heteroaryl is indazolyl optionally substituted with one or two R7independently selected from alkoxy, haloalkyl, and C1-C6 alkyl. In one embodiment, R4is heteroaryl, wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionally substituted with one or more R7. In one embodiment, R4is heteroaryl, wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionally substituted with one or more R7independently selected from amino, hydroxyl, Cl - C3alkyl, and hydroxyl. In one embodiment, the R4heteroaryl is a pyridinyl optionally substituted with one or more R7. In one embodiment, the R4heteroaryl is pyridinyl optionally substituted with one or more R7independently selected from Cl - C3 alkyl, halogen and haloalkyl. In one embodiment, the R4heteroaryl is benzo[d]thiazolyl optionally substitutedwith one or more R7, such as hydroxyl, one or two Cl - C3 alkyl, or hydroxyl and one or two Cl - C3 alkyl. In one embodiment, the R4heteroaryl is indolyl optionally substituted with one or more R7. In one embodiment, the R4heteroaryl is indolyl optionally substituted with one or two R7independently selected from hydroxyl and Cl - C3alkyl. In one embodiment, R11is methyl. In one embodiment, the piperidinyl ring is unsubstituted. In one embodiment, the piperidinyl ring is substituted with R8. In one embodiment, R8is Cl - C3 alkyl optionally substituted with cyano or hydroxyl. In one embodiment, R8is methyl, cyanomethyl or hydroxymethyl. In one embodiment, R8is methyl. In one embodiment, R8is cyanomethyl. In one embodiment, R8is hydroxymethyl. In another embodiment, R5and R10are each Cl - C3 alkyl, R1 1is methyl, R8is methyl, cyanomethyl or hydroxymethyl, L is a bond, and R4is aryl or heteroaryl, each optionally substituted with one or more R6or R7.

[0126] In one embodiment, Formula I includes compounds having the Formula I-B:Formula I-B and R1, R3, R4, R9, L and m are as defined for Formula I, R2is heterocyclylalkyl optionally substituted with one or more R9, and the piperidinyl ring is optionally substituted with R8, where R8is as defined for Formula I. In one embodiment, the heterocyclyl portion of the R2heterocyclylalkyl is a monocyclic, bicyclic, or bridged ring system having one or two ring heteroatoms independently selected from N and O. In one embodiment, R2heterocyclyl is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1 ,4-oxazepanyl, thiomorpholinyl-l , l - dioxide, 3-azabicyclo[3.1 .OJhexanyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, andazabicyclo[2.2. l ]heptan-2-yl, optionally substituted with one or more R9. In one embodiment,each R9is selected from acyl, oxo, halogen, cyano, Cl - C3 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, heterocyclyl, cycloalkyl, aralkyl and dialkylamidoalkyl. In one embodiment, L is a bond. In one embodiment, R4is aryl or heteroaryl, each of which is optionally substituted with one or more R6or R7. In one embodiment, R4is aryl or heteroaryl, each of which is optionally substituted with one or more R7. In one embodiment, each R7is independently selected from hydroxyl, amino, halogen, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, cycloalkyl and alkoxy. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl, trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl and trifluoromethylthio. In one embodiment, the aryl is phenyl substituted with one to three R7groups independently selected from hydroxyl, fluorine and chlorine. In one embodiment, the aryl is phenyl substituted with hydroxyl and Cl - C3 alkyl or two Cl— C3 alkyl. In one embodiment, the aryl is phenyl substituted with Q-haloalkyl and hydroxyl or fluorine. In one embodiment, the aryl is naphthyl substituted with one or more R7groups independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is naphthyl substituted with one or more R7groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, R4is naphthyl optionally substituted with one or more R7substituents independently selected from hydroxyl, halogen, Cl - C3 alkyl, amino, and haloalkyl. In one embodiment, R4is naphthyl optionally substituted with one to three R7substituents independently selected from difluoromethyl, methyl, hydroxyl, amino, fluoro, and chloro. In one embodiment, the aryl is naphthyl optionally substituted with one or more halogen. In one embodiment, the aryl is naphthyl substituted with hydroxyl and trifluoromethyl or Cl - C3alkyl. In one embodiment, the aryl is naphthyl substituted with hydroxyl. In one embodiment, R4is heteroaryl, wherein the heteroaryl is indazolyl optionally substituted with one or two R7independently selected from alkoxy, haloalkyl, and C1-C6 alkyl. In one embodiment, R4is heteroaryl, wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionally substituted with one or more R7. In one embodiment, R4is heteroaryl, wherein theheteroaryl is quinolinyl or isoquinolinyl, each optionally substituted with one or more R7independently selected from amino, hydroxyl, Cl - C3 alkyl, and hydroxyl. In oneembodiment, the R4heteroaryl is a pyridinyl optionally substituted with one or more R7. In one embodiment, the R4heteroaryl is pyridinyl optionally substituted with one or more R7independently selected from Cl - C3 alkyl, halogen and haloalkyl. In one embodiment, the R4heteroaryl is benzo[d]thiazolyl optionally substituted with one or more R7, such as hydroxyl, one or two Cl - C3 alkyl, or hydroxyl and one or two Cl - C3 alkyl. In one embodiment, the R4heteroaryl is indolyl optionally substituted with one or more R7. In one embodiment, the R4heteroaryl is indolyl optionally substituted with one or two R7independently selected from hydroxyl and Cl - C3 alkyl. In one embodiment, R11is methyl. In one embodiment, the piperidinyl ring is unsubstituted. In one embodiment, the piperidinyl ring is substituted with R8. In one embodiment, the piperidinyl ring is unsubstituted. In one embodiment, the piperidinyl ring is substituted with R8. In one embodiment, R8is Cl - C3 alkyl optionally substituted with cyano, hydroxyl or methoxy. In one embodiment, R8is methyl, cyanomethyl, hydroxymethyl or methoxymethyl.

[0127] In one embodiment, X is a saturated bridged ring system. Nonlimiting examples of bridged ring systems include diazabicycloheptanes and diazabicyclooctanes. In certain embodiments, when X is a saturated bridged ring system, R1is -C(0)CH=CH2. In one embodiment, the bridged ring system is substituted with one or two groups independently selected from R8, where R8is as defined for Formula I. In one embodiment, the bridged ring system is unsubstituted. In one embodiment, the bridged ring system isdiazabicyclo [3.2.1 ]octan-8-yl or diazabicyclo [3.2.1] octan-3 -yl .

[0128] In one embodiment, R’-X is:

[0129] wherein A and B are a spirocyclic ring system, wherein A and B are the same or different and independently represent a 4-6 membered saturated ring systems, wherein the rings are optionally substituted with one or more R8, wherein R8is as defined for Formula I. In certain embodiments, R1is -C(0)CH=CH2. In certain embodiments, rings A and B are unsubstituted.

[0130] In one embodiment, the spirocyclic ring system is unsubstituted. Non-limiting examples of spirocyclic ring systems include:

[0131] In certain embodiments when A and B represent a spirocyclic ring system, R1is - C(0)CH=CH2.

[0132] In one embodiment of Formula I, R2is selected from the group consisting ofhydroxyalkyl, dialkylaminylalkyl, heterocyclyl and heterocyclylalkyl, wherein each of the heterocyclyl or heterocyclylalkyl are independently optionally substituted with R9. In another embodiment, R2is heterocyclyl and heterocyclylalkyl, wherein each of the heterocyclyl or heterocyclylalkyl are independently optionally substituted with one or more R9. In certain embodiments, R2is dialkylaminylalkyl optionally substituted with one or more R9. Non limiting examples include dimethylaminylethyl, dimethylaminylpropanyl,dimethylaminylpropan-2-yl, dimethylaminylbutanyl, dimethylaminylbutan-2-yl, 2- dimethylaminylpropanol, or diethylaminylethyl.

[0133] In one embodiment, Y is O and R2is selected from the group consisting of hydroxyalkyl, dialkylaminylalkyl, heterocyclyl, heterocyclylalkyl, and -ZR5R10, wherein R5and R10are as defined for Formula I.

[0134] In one embodiment, Y is O and R2is selected from the group consisting of hydroxyalkyl, dialkylaminylalkyl, heterocyclyl and heterocyclylalkyl, wherein each of the heterocyclyl or heterocyclylalkyl are independently optionally substituted with R9. In another embodiment, R2is heterocyclyl and heterocyclylalkyl, wherein each of the heterocyclyl or heterocyclylalkyl are independently optionally substituted with one or more R9. Non-limiting examples of R9include acyl, oxo, halogen, cyano, Cl - C6 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, aralkyl or dialkylamidoalkyl. In certain embodiments, R2is dialkylaminylalkyl optionally substituted with one or more R9. Non-limiting examples include dimethylaminylethyl,dimethylaminylpropanyl, dimethylaminylpropan-2-yl, dimethylaminylbutanyl,dimethylaminylbutan-2-yl, 2-dimethylaminylpropanol, or diethylaminylethyl.

[0135] In one embodiment of Formula I, R4is aryl optionally substituted with one or more R6or R7. In one embodiment, R4is phenyl or naphthyl optionally substituted with one or more R6or R7. In one embodiment, R4is phenyl or naphthyl optionally substituted with one or more R7. In one embodiment, R4is phenyl or naphthyl optionally substituted with one or more R7substituents independently selected from halogen, hydroxyl, Cl - C3alkyl, cycloalkyl, alkoxy,haloalkyl, or Q-haloalkyl wherein Q is O or S. In one embodiment, R4is phenyl or naphthyl optionally substituted with one or more R7substituents independently selected from methyl, trifluoromethyl, hydroxyl, trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl and methylthio.

[0136] In one embodiment, R4is isoquinolinyl which is optionally substituted with amino. In one embodiment, R4is aralkyl. In certain embodiments, the aralkyl is benzyl. In one embodiment, the aralkyl is benzyl wherein the alkyl portion is substituted with hydroxyl or hydroxyalkyl.

[0137] Nonlimiting examples of compounds of Formula (I), Formula I-A and Formula I-B are selected from the group consisting of:31323334353637384041424344454955565758596063656667

[0138] and pharmaceutically acceptable salts thereof.

[0139] Further nonlimiting examples of compounds of Formula (I), Formula I-A and Formula I- B are selected from the group consisting of:737577798586

[0140] and pharmaceutically acceptable salts thereof.

[0141] In one aspect of the invention, compounds are provided represented by formula (II):Formula (II)

[0142] or a pharmaceutically acceptable salt thereof:

[0143] wherein:

[0144] X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R8;

[0145] Y is a bond, O, S or NR5;

[0147] R2is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl,dialkylaminylalkyl, -Z-NR5R10, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, orheteroarylalkyl, wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R9;

[0148] each Z is Cl - C4 alkylene;

[0149] each R3is independently Cl - C3 alkyl, oxo, haloalkyl, hydroxyl or halogen;

[0150] L is a bond, -C(O)-, or Cl - C3 alkylene;

[0151] R4is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R6, R7or R8;

[0152] each R5is independently hydrogen or Cl - C3 alkyl;

[0153] R6is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R7;

[0154] each R7is independently halogen, hydroxyl, Cl - C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;

[0155] R8is oxo, Cl - C3 alkyl, C2 - C4 alkynyl, heteroalkyl, cyano, -C(0)OR5, -C(0)N(R5)2, - N(R5)2, wherein the Cl - C3 alkyl may be optionally substituted with cyano, halogen, -OR5, - N(R5)2, or heteroaryl;

[0156] each R9is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen,Cl - C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the Cl - C6 alkyl may be optionally substituted with cycloalkyl;

[0157] each R10is independently hydrogen, acyl, Cl - C3 alkyl, heteroalkyl or hydroxyalkyl;

[0158] R1 1is haloalkyl;

[0159] RAis absent, hydrogen, deuterium, cyano, halogen, Cl - C-3 alkyl, haloalkyl, heteroalkyl, -C(0)N(R5)2, or hydroxyalkyl;

[0160] each RBis independently hydrogen, deuterium, cyano, Cl - C3 alkyl, hydroxyalkyl, heteroalkyl, Cl - C3 alkoxy, halogen, haloalkyl, -ZNR5R! 1, -C(0)N(R5)2, -NHC(0)C1 - C3 alkyl, -CH2NHC(0)C1 - C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and Cl - C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R7;

[0161] or when z== js adouble bond and p is two, one RBis hydrogen and RAand one RBand the carbon atoms to which they are attached form a 4-8 membered partially saturated cycloalkyl substituted with oxo;

[0162] m is zero or an integer between 1 and 2;

[0163] p is one or two; and wherein,

[0164] when— — is a triple bond then RAis absent, p equals one and RBis hydroxyalkyl,

[0165] or when . is a double bond then RAis present, RBis present and p equals two, wherein when RAis hydrogen or Cl - C3 alkyl, at least one RBis deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, -ZNR5Rn, -C(0)N(R5)2, - NHC(0)Cl - C3 alkyl, -CH2NHC(0)C1 - C3 alkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and Cl - C3 alkyl; or when each RBis hydrogen, then RAis deuterium, cyano, halogen, haloalkyl, -C(0)N(R5)2, hydroxyalkyl or heteroalkyl.

[0166] In certain embodiments, RJ-X is:

[0167] wherein R1is are defined for Formula II and the piperazinyl ring is optionally substituted with R8, where R8is as defined for Formula II. In certain embodiments, R8is Cl - C3 alkyl wherein the alkyl is optionally substituted with cyano or OR5, or -C(0)N(R5)2,wherein each R5is independently hydrogen or Cl - C3 alkyl.

[0168] In particular embodiments, R1is -C(0)C(RA) - C(RB)Pwhere RA, RBand p are as defined for Formula II. In one embodiment, R1is -C(0)C(RA):= C(RB)P, wherein.is a triple bond and RAis absent, p is one and RBis hydroxyalkyl.

[0169] In one embodiment, R1is -C(0)C(RA):=^=C(RB)P, wherein=:^=is a double bond and RAis hydrogen or Cl - C3 alkyl, p is two and at least one RBis deuterium, cyano, Cl - C3 alkyl, hydroxyalkyl, heteroalkyl, Cl - C3 alkoxy, halogen, haloalkyl, -ZNR5Rn, -C(0)N(R5)2, - NHC(0)Cl - C3 alkyl, -CH2NHC(0)C1 - C3 alkyl, heteroaryl, heteroarylalkyl,dialkylaminylalkyl, or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and Cl - C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R7. In one embodiment, when == is a double bond, the double bond is in the E configuration. In one embodiment, the double bond is in the Z configuration.

[0170] In certain embodiments, one RBis heterocyclylalkyl substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy or Cl - C3 alkyl and the other RBis hydrogen. In one embodiment, the heterocyclyl portion of the heterocyclylalkyl is azetidinyl substituted with a halogen. In certain embodiments, the halogen is fluorine. In one embodiment, the heterocyclyl portion of the heterocyclylalkyl is pyrrolidinyl substituted with one or more halogen. In certain embodiments, the halogen-substituted pyrrolidinyl is fluoropyrrolidinyl or difluorpyrrolidinyl.

[0171] In certain embodiments, one RBis halogen and the other RBis hydrogen. In one embodiment, the halogen is chlorine.

[0172] In certain embodiments, one RBis haloalkyl and the other RBis hydrogen. In one embodiment, the haloalkyl is chloromethyl, fluoromethyl, difluoromethyl or trifluoromethyl.

[0173] In certain embodiments, one RBis heteroalkyl and the other RBis hydrogen. In one embodiment, the heteroalkyl is methoxymethyl.

[0174] In ceratin embodiments, one RBis -ZNR R1 1, wherein Z is methylene, R5is methyl and R1 1is trifluoromethyl or 2,2,2-trifluoroethyl, and the other RBis hydrogen.

[0175] In certain embodiments, one RBis hydroxyalkyl and the other RBis hydrogen.

[0176] ln certain embodiments, one RBis heteroaryl optionally substituted with one or more R7and the other RBis hydrogen. In one embodiment, the heleroaryl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, each substituted with one or more R7.

[0177] In certain embodiments, one RBis heteroarylalkyl optionally substituted with one or more R7, and the other RBis hydrogen. In one embodiment, the heteroaryl portion of theheteroarylalkyl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, each optionally substituted with one or more R7. In one embodiment, the one or more R7is Cl - C3 alkyl.

[0178] In certain embodiments, one RBis -C(0)N(R5)2and the other RBis hydrogen. In one embodiment, each R5is hydrogen. In one embodiment, each R5is Cl - C3 alkyl.

[0179] In certain embodiments, one RBis -NHC(0)Cl - C3 alkyl or -CH2NHC(0)C1 - C3 alkyl and the other RBis hydrogen. In one embodiment, the Cl - C3 alkyl is methyl.

[0180] In one embodiment, R1is -C(0)C(RA) =C(RB)P, wherein RAis deuterium, cyano, halogen, Cl - C-3 alkyl, haloalkyl, heteroalkyl, -C(0)N(R5)2, or hydroxyalkyl, p is two, each RBis hydrogen. In one embodiment, RAis halogen. In one embodiment, the halogen is fluorine or chlorine. In one embodiment, RAis haloalkyl. In one embodiment, the haloalkyl istrifluoromethyl. In one embodiment, RAis cyano. In one embodiment, RAis heteroalkyl. In one embodiment, the heteroalkyl is methoxy. In one embodiment, RAis hydroxyalkyl.

[0181] In one embodiment, R1is -C(0)C(RA) == C(RB)P, wherein . is a double bond and RAis deuterium, p is two and at least one RBis deuterium.

[0182] In one embodiment, R1is -C(0)C(RA)C(RB)P, whereinis a double bond and p is two, one RBis hydrogen and RAand one RBand the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl substituted with oxo.

[0183] In one embodiment, R1is -C(0)C(RA) C(RB) , wherein — is a double bond and p is two, one RBis hydrogen, the second RBis dialkylaminylalkyl, and RAis halogen

[0184] In one embodiment, Y is O or NR5and R2is heterocyclyl or heterocyclyl alkyl optionally substituted with one or more R9. Nonlimiting examples of one or more R9when R2is heterocyclyl or heterocyclylalkyl include Cl - C3 alkyl, acyl, oxo, cyano, alkoxy, cycloalkyl, cycloalkylmethyl, halogen, and hydroxyl. Nonlimiting examples of R2heterocyclyls optionally substituted with one or more R9include azetidinyl, C1-C3 alkyl-substituted azetidinyl (e.g., methylazetidinyl), halo-substituted azetidinyl (e.g., difluoroazetidinyl), tetrahydropyran, pyrrolidinyl, C1-C3 alkyl-substituted pyrrolidinyl (e.g., methylpyrrolidinyl,dimethylpyrrolidinyl, and isopropylpyrrolidinyl), cycloalkylalkylpyrrolidinyl,hydroxypyrrolindinyl, halo-substituted pyrrolidinyl (e.g., fluoropyrrolidinyl anddifluoropyrrolidinyl), halo-substituted N-methyl pyrrolidinyl (e.g., N-methylfluoropyrrolidinyl and N-methyldifluoropyrrolidinyl), methoxyethylpyrrolidinyl, alkoxy-substituted N- methylpyrrolidinyl (e.g., (N-methyl)methoxypyrrolidinyl), piperazinyl,dimethylaminylpyrrolidinyl, morpholinyl, methylmorpholinyl, 1 ,4-oxazepanyl, piperdinyl, Cl- C3 alkyl-substituted piperidinyl (e.g., methylpiperidinyl), acylpiperdinyl, cyanopiperdinyl, cycloalkylpiperdinyl, halopiperdinyl (e.g., fluoropiperdinyl), dihalopiperdinyl (e.g.,difluoropiperdinyl), alkoxypiperdinyl, pyrrolidonyl, piperidonyl, thiomorpholinyl- 1 ,1 -dioxide, 3-azabicyclo[3.1.0]hexanyl, oxa-5-azabicyclo[2.2.l]heptan-5-yl, and azabicyclo[2.2.1]heptan-2- yi-

[0185] In one embodiment, the heterocycyl portion of the heterocyclylalkyl is N- methylpyrrolidinyl. In one embodiment, the heterocycyl portion of the heterocyclylalkyl is 3,3- difluoro-1 -methylpyrrolidinyl.

[0186] In certain other embodiments, R4is aryl. In one embodiment, R4is selected from the group consisting of phenyl and naphthyl and is optionally substituted with one or more R6or R7. Examples of R7substituents include halogen, hydroxyl, Cl - C6 alkyl (e.g., Cl - C3 alkyl), cycloalkyl, haloalkyl, Q-haloalkyl, amino, cyano, hydroxyalkyl and alkoxy. In oneembodiment, the aryl is phenyl substituted with one or more R7groups independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from methyl,trifluoromethyl, hydroxyl, fluoro, and chloro. In one embodiment, the aryl is phenyl substituted with one to three R7groups independently selected from methyl, hydroxyl, trifluoromethyl, fluorine and chlorine. In one embodiment, the aryl is phenyl substituted with hydroxyl and Cl - C3 alkyl or two Cl - C3 alkyl. In one embodiment, the aryl is phenyl substituted with trifluoromethyl and Cl - C3 alkyl or two Cl - C3 alkyl.

[0187] In one embodiment, R4is aryl wherein aryl is naphthyl optionally substituted with one or more R7. In one embodiment, the aryl is naphthyl substituted with one or more R7groups independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is naphthyl substituted with one or more R7groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, R4is naphthyl optionally substituted with one or more R7substituents independently selected from hydroxyl, halogen, Cl - C3 alkyl, amino, and haloalkyl. In one embodiment, R4is naphthyl optionally substituted with one to three R7substituents independently selected from difluoromethyl, methyl, hydroxyl, amino, fluoro, and chloro. In one embodiment, the substituted naphthyl is 8-chloronaphthyl or 8-methylnaphthyl.

[0188] In one embodiment, the aryl is naphthyl optionally substituted with one or more halogen. In one embodiment, the aryl is naphthyl substituted with hydroxyl and trifluoromethyl or Cl - C3alkyl. In one embodiment, the aryl is naphthyl substituted with hydroxyl.

[0189] In one embodiment, R4is heteroaryl optionally substituted with one or more R6, R7or R8. In one embodiment, R4is heteroaryl optionally substituted with one or more R7or R8independently selected from halogen, hydroxyl, C l - C3 alkyl, haloalkyl, Q-haloalkyl, alkoxy and amino. In one embodiments, R4is indoyl, indazolyl, quinolinyl, isoquinolinyl, pyridinyl or benzo[d]thiazolyl optionally substituted with one or more R6, R7or R8. In one embodiments, R4is indoyl, indazolyl, quinolinyl, isoquinolinyl, pyridinyl or benzo[d]thiazolyl optionally substituted with one or more R7or R8independently selected from oxo, halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, alkoxy and amino.

[0190] In yet other embodiments, R4is heteroaryl, optionally an indoyl or an indazolyl, each of which may be substituted with one or more R6, R7or R8. In one embodiment, R4is heteroaryl optionally substituted with one or more R7or R8substituents independently selected from thegroup consisting of halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl and alkoxy. In one embodiment, the R4heteroaryl is indazolyl optionally substituted with one or two R7or R8independently selected from oxo, triiluoromethyl, alkoxy, haloalkyl, and C1-C6 alkyl. In other embodiments, the R4heteroaryl is a quinolinyl or isoquinolinyl, each optionally substituted with one or more R7. In one embodiment, the R4heteroaryl is a quinolinyl or isoquinolinyl, each optionally substituted with one or more R7independently selected from amino, hydroxyl, Cl - C3 alkyl, and hydroxyl. In one embodiment, the R4heteroaryl is a quinolinyl or isoquinolinyl, each optionally substituted with R7selected from hydroxyl and amino. In one embodiment, the R4heteroaryl is a pyridinyl optionally substituted with one or more R6, R7or R8. In one embodiment, the R4heteroaryl is pyridinyl optionally substituted with one or more R7independently selected from Cl - C3 alkyl, halogen and haloalkyl. In one embodiment, the R4heteroaryl is indolyl optionally substituted with one or more R6, R7or R8. In one embodiment, the R4heteroaryl is indolyl optionally substituted with one or two R7independently selected from hydroxyl, trifluoromethyl and Cl - C3alkyl.

[0191] In one embodiment, L is a bond.

[0192] In one embodiment, m is zero.

[0193] In one embodiment, R8is heteroalkyl, C2-C4 alkynyl or Cl - C3 alkyl optionally substituted with -OR5, cyano or heteroaryl. In one embodiment, R8is methyl, cyanomethyl, methoxymethyl, hydroxymethyl. In one embodiment, R8is methyl. In one embodiment, R8is cyanomethyl. In one embodiment, R8is hydroxymethyl.

[0194] In one embodiment, Formula II includes compounds having the Formula II-A:

[0195] wherein R1, R3, R4, R5, R10, L and m are as defined for Formula II, R11is hydrogen, methyl or hydroxyalkyl, and the piperazinyl ring is optionally substituted with R8wherein R8is as defined for Formula II.

[0196] In particular embodiments, R1is - C(0)C(RA) - C(RB)Pwhere RA, RBand p are as defined for Formula II. In one embodiment, R1is -C(0)C(RA) . C(RB)P, wherein .is a triple bond and RAis absent, p is one and RBis hydroxyalkyl.

[0197] In one embodiment, R1is -C(0)C(RA)— . - . - C(RB)P, wherein .. - is a double bond and RAis hydrogen or Cl - C3 alkyl, p is two and at least one RBis deuterium, cyano, Cl - C3 alkyl, hydroxyalkyl, heteroalkyl, Cl - C3 alkoxy, halogen, haloalkyl, -ZNR^11, -C(0)N(R5)2, - NHC(0)C1 - C3 alkyl, -CH2NHC(0)C1 - C3 alkyl, heteroaryl, heteroarylalkyl, orheterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and Cl - C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R7.

[0198] In one embodiment, R1is -C(0)C(RA) =C(RB)P, wherein RAis deuterium, cyano, halogen, haloalkyl, heteroalkyl, -C(0)N(R5)2, or hydroxyalkyl, p is two, and each RBis hydrogen. In one embodiment, RAis halogen. In one embodiment, the halogen is fluorine or chlorine. In one embodiment, RAis haloalkyl. In one embodiment, the haloalkyl istrifluoromethyl. In one embodiment, RAis cyano. In one embodiment, RAis heteroalkyl. In one embodiment, the heteroalkyl is methoxymethyl. In one embodiment, RAis hydroxyalkyl.

[0199] In one embodiment, R1is -C(0)C(RA)— . - . C(RB)P, wherein — - . is a double bond and RAis deuterium, p is two and at least one RBis deuterium.

[0200] In one embodiment, R1is -C(0)C(RA) = C(RB)P, wherein— .— is a double bond and p is two, one RBis hydrogen and RAand one RBand the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl substituted with oxo.

[0201] In one embodiment, R1is -C(0)C(RA) - C(RB)P, wherein is a double bond and p is two, one RBis hydrogen, the second RBis dialkylaminylalkyl, and RAis halogen.

[0202] In one embodiment, L is a bond. In one embodiment, R4is aryl or heteroaryl, each of which is optionally substituted with one or more R6, R7or R8. In one embodiment, R4is aryl or heteroaryl, each of which is optionally substituted with one or more R7. In one embodiment, each R7or R8is independently selected from oxo, hydroxyl, amino, halogen, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, cycloalkyl and alkoxy. In one embodiment, R5and R10are each Cl - C3 alkyl. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl,trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl and trifluoromethylthio. In one embodiment, the aryl is phenyl substituted with one to three R7groups independently selected from hydroxyl, fluorine and chlorine. In one embodiment, the aryl is phenyl substituted with hydroxyl and Cl - C3 alkyl or two Cl - C3 alkyl. In one embodiment, the aryl is phenyl substituted with Q-haloalkyl and hydroxyl or fluorine. In one embodiment, the aryl is naphthyl substituted with one or more R7groups independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is naphthyl substituted with one or more R7groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, R4is naphthyl optionally substituted with one or more R7substituents independently selected from hydroxyl, halogen, Cl - C3 alkyl, amino, and haloalkyl. In one embodiment, R4is naphthyl optionally substituted with one to three R7or R8substituents independently selected from difluoromethyl, methyl, hydroxyl, amino, fluoro, and chloro. In one embodiment, the aryl is naphthyl optionally substituted with one or more halogen. In one embodiment, the aryl is naphthyl substituted with hydroxyl and trifluoromethyl or Cl - C3alkyl. In one embodiment, the aryl is naphthyl substituted with hydroxyl. In one embodiment, R4is heteroaryl, wherein the heteroaryl is indazolyl optionally substituted with one or two R7or R8independently selectedfrom oxo, alkoxy, haloalkyl, and C1 -C6 alkyl. In one embodiment, R4is heteroaryl, wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionally substituted with one or more R7.In one embodiment, R4is heteroaryl, wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionally substituted with one or more R7independently selected from amino, hydroxyl, Cl - C3alkyl, and hydroxyl. In one embodiment, the R4heteroaryl is a pyridinyl optionally substituted with one or more R6, R7or R8. In one embodiment, the R4heteroaryl is pyridinyl optionally substituted with one or more R7independently selected from Cl - C3 alkyl, halogen and haloalkyl. In one embodiment, the R4heteroaryl is indolyl optionally substituted with one or more R7. In one embodiment, the R4heteroaryl is indolyl optionally substituted with one or two R7independently selected from hydroxyl and Cl - C3alkyl. In one embodiment, R1 1is methyl. In one embodiment, the piperazinyl ring is unsubstituted. In one embodiment, the piperazinyl ring is substituted with R8. In one embodiment, R8is Cl - C3 alkyl optionally substituted with cyano or hydroxyl. In one embodiment, R8is methyl, cyanomethyl or hydroxymethyl. In one embodiment, R8is methyl. In one embodiment, R8is cyanomethyl. In one embodiment, R8is hydroxymethyl. In another embodiment, R5and R10are each Cl - C3 alkyl, R1 1is methyl, R8is methyl, cyanomethyl or hydroxymethyl, L is a bond, and R4is aryl or heteroaryl, each optionally substituted with one or more R6or R7.

[0203] In one embodiment, Formula II includes compounds having the Formula II-B:Formula II-B

[0204] where R1, R3, R4, L and m are as defined for Formula II, R2is heterocyclylalkyl optionally substituted with one or more R9wherein R9is as defined for Formula II, and the piperazinyl ring is optionally substituted with R8, where R8is as defined for Formula II.

[0205] In particular embodiments, R1is -C(0)C(RA) - C(RB)Pwhere RA, RBand p are as defined for Formula II. In one embodiment, R1is -C(0)C(RA) C(RB)P, wherein is a triple bond and RAis absent, p is one and RBis hydroxyalkyl.

[0206] In one embodiment, R1is -C(0)C(RA) = C(RB)P, wherein -.is a double bond and RAis hydrogen or Cl - C3 alkyl, p is two and at least one RBis deuterium, cyano, Cl - C3 alkyl, hydroxyalkyl, heteroalkyl, Cl - C3 alkoxy, halogen, haloalkyl, -ZNR5Rn, -C(0)N(R5)2, - NHC(0)C1 - C3 alkyl, -CH2NHC(0)Cl - C3 alkyl, heteroaryl, heteroarylalkyl, orheterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and Cl - C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R7.

[0207] In one embodiment, R1is -C(0)C(RA) =C(RB)P, wherein RAis deuterium, cyano, halogen, haloalkyl, heteroalkyl, -C(0)N(R5)2, or hydroxyalkyl, p is two, and each RBis hydrogen. In one embodiment, RAis halogen. In one embodiment, the halogen is fluorine or chlorine. In one embodiment, RAis haloalkyl. In one embodiment, the haloalkyl istrifluoromethyl. In one embodiment, RAis cyano. In one embodiment, RAis heteroalkyl. In one embodiment, the heteroalkyl is methoxymethyl. In one embodiment, RAis hydroxyalkyl.

[0208] In one embodiment, R1is -C(0)C(RA).C(RB)P, wherein - is a double bond and RAis deuterium, p is two and at least one RBis deuterium.

[0209] In one embodiment, R1is -C(0)C(RA).C(RB)P, wherein—.is a double bond and p is two, one RBis hydrogen and RAand one RBand the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl substituted with oxo.

[0210] In one embodiment, R1is -C(0)C(RA).C(RB)P, wherein—.is a double bond and p is two, one RBis hydrogen, the second RBis dialkylaminylalkyl, and RAis halogen.

[0211] In one embodiment, the heterocyclyl portion of the R2heterocyclylalkyl is a monocyclic, bicyclic, or bridged ring system having one or two ring heteroatoms independently selected from N and O. In one embodiment, R2heterocyclyl is azetidinyl, methylazetidinyl,ethylazetidinyl, isopropylazetidinyl, difluoroazetidinyl, cyclopropylazetidinyl,tetrahydropyranylazetidinyl, tetrahydropyran, pyrrolidinyl, methylpyrrolidinyl,diemethylpyrrolidinyl, isopropylpyrrolidinyl, cycloalkylalkylpyrrolidinyl,hydroxypyrrolindinyl, fluoropyrrolidinyl, difluoropyrrolidinyl, (N-methyl)fluoropyrrolidinyl, (N-methyl)difluoropyrrolidinyl, methoxyethylpyrrolidinyl, alkoxy-substituted N- methylpyrrolidinyl (e.g., (N-methyl)methoxypyrrolidinyl), piperazinyl,dimethylaminylpyrrolidinyl, pyrrolidinone, methylpyrrolidinone, morpholinyl,methylmorpholinyl, ethylmorpholinyl, isopropylmorpholinyl, oxetanyl, l,4-oxazepanyl, piperdinyl, methylpiperidinyl acylpiperdinyl, cyanopiperdinyl, cycloalkylpiperdinyl, halopiperdinyl, dihalopiperdinyl, fluoropiperdinyl, difluoropiperdinyl, alkoxypiperdinyl, pyrrolidonyl, piperidinonyl, tetrahydropyrrolizinyl, thiomorpholinyl- 1,1 -dioxide, 3- azabicyclo[3.1.0]hexanyl, oxa-5-azabicyclo[2.2.l]heptan-5-yl, or azabicyclo[2.2.l]heptan-2-yl, optionally substituted with one or more R9. In one embodiment, each R9is selected from acyl, oxo, halogen, cyano, Cl - C3 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, aralkyl, heterocyclyl and dialkylamidoalkyl. In one embodiment, L is a bond. In one embodiment, the heterocyclyl portion of the R2heterocyclylalkyl is (N-methyl)difluoropyrrolidinyl, including 3, 3-difluoro-l -methylpyrrolidinyl. In one embodiment, the heterocyclyl portion of the R2heterocyclylalkyl is N-methylpyrrolidinyl.

[0212] In one embodiment, R4is aryl or heteroaryl, each of which is optionally substituted with one or more R6, R7or R8. In one embodiment, R4is aryl or heteroaryl, each of which is optionally substituted with one or more R7. In one embodiment, each R7is independently selected from hydroxyl, amino, halogen, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, cycloalkyl and alkoxy. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is phenyl substituted with one or more R7groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, the aryl is phenyl substituted with one or more R7groupsindependently selected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl, trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl and trifluoromethylthio. In one embodiment, the aryl is phenyl substituted with one to three R7groups independently selected from hydroxyl, fluorine and chlorine. In one embodiment, the aryl is phenyl substituted with hydroxyl and Cl - C3 alkyl or two Cl - C3 alkyl. In one embodiment, the aryl is phenyl substituted with Q-haloalkyl and hydroxyl or fluorine. In one embodiment, the aryl is naphthyl substituted with one or more R7groups independently selected from halogen, hydroxyl, Cl - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is naphthyl substituted with one or more R7groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, R4is naphthyl optionally substituted with one or more R7substituents independently selected from hydroxyl, halogen, Cl— C3 alkyl, amino, and haloalkyl. In one embodiment, R4is naphthyl optionally substituted with one to three R7substituents independently selected fromdifluoromethyl, methyl, hydroxyl, amino, fluoro, and chloro. In one embodiment, the aryl is naphthyl optionally substituted with one or more halogen. In one embodiment, the aryl is naphthyl substituted with hydroxyl and trifluoromethyl or Cl - C3 alkyl. In one embodiment, the aryl is naphthyl substituted with hydroxyl. In one embodiment, R4is heteroaryl, wherein the heteroaryl is indazolyl optionally substituted with one or two R7independently selected from alkoxy, haloalkyl, and C1-C6 alkyl.

[0213] In one embodiment, R4is heteroaryl, wherein the heteroaryl is quinolinyl orisoquinolinyl, each optionally substituted with one or more R6, R7or R8. In one embodiment, R4is heteroaryl, wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionally substituted with one or more R6, R7or R8independently selected from oxo, amino, hydroxyl,Cl— C3 alkyl, and hydroxyl. In one embodiment, the R4heteroaryl is a pyridinyl optionally substituted with one or more R6, R7or R8. In one embodiment, the R4heteroaryl is pyridinyl optionally substituted with one or more R7independently selected from Cl - C3 alkyl, halogen and haloalkyl. In one embodiment, the R4heteroaryl is indolyl optionally substituted with one or more R6, R7or R8. In one embodiment, the R4heteroaryl is indolyl optionally substituted with one or two R7independently selected from hydroxyl and Cl - C3 alkyl. In one embodiment, R1 1is methyl. In one embodiment, the piperazinyl ring is unsubstituted. In oneembodiment, the piperazinyl ring of Formula II-B is substituted with R8. In one embodiment, R8is Cl - C3 alkyl optionally substituted with cyano, hydroxyl or methoxy. In oneembodiment, R8is methyl, cyanomethyl, hydroxymethyl or methoxymethyl.

[0214] Nonlimiting examples of compounds of Formula (II), Formula II-A and Formula II-B are selected from the group consisting of:113114126127128

[0215] or a pharmaceutically acceptable salt thereof.

[0216] In one embodiment, the compounds of Formula I include trifluoroacetic acid salts of the above compounds. The compounds of Formula (I), Formula I-A, Formula I-B, Formula (II), Formula II-A, or Formula II-B may be formulated into pharmaceutical compositions.PHARMACEUTICAL COMPOSITIONS

[0217] In another aspect, the invention provides pharmaceutical compositions comprising a KRas G12C inhibitor according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, withoutlimitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain embodiments, compounds of the invention are administered intravenously in a hospital setting. In one embodiment, administration may be by the oral route.

[0218] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa.,1990.

[0219] As used herein, the term pharmaceutically acceptable salt refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula— NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

[0220] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. In one embodiment, a dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg / kg, forexample 0.1 to 100 mg / kg per day, and as a further example 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt / wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.

[0221] The pharmaceutical compositions comprising compounds of the present invention may be used in the methods of use described herein.METHODS OF USE

[0222] In yet another aspect, the invention provides for methods for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula (II), Formula II-A, or Formula II- B, pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0223] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a KRas G12C with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12C, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12C.

[0224] In one embodiment, a cell in which inhibition of KRas G12C activity is desired is contacted with an effective amount of a compound of Formula (II), Formula II-A, or Formula II-B, to negatively modulate the activity of KRas G12C. In other embodiments, atherapeutically effective amount of pharmaceutically acceptable salt or pharmaceutical compositions containing the compound of Formula (II), Formula II-A, or Formula II-B, may be used.

[0225] By negatively modulating the activity of KRas G12C, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12C activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12C. The degree of covalent modification of KRas G12C may be monitored in vitro using well known methods, including those described in Example A below. In addition, the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12C activity of the amount of phosphylated ERK, including those described in Example B below, to assess the effectiveness of treatment and dosages may be adjusted accordingly by the attending medical practitioner.

[0226] In another aspect, methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I), Formula ITA, or Formula II-B, pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are provided.

[0227] The compositions and methods provided herein may be used for the treatment of a KRas G12C-associated cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (II), Formula II-A, or Formula II-B, pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are provided. In one embodiment, the KRas Gl2C-associated cancer is lung cancer.

[0228] The compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell,undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor(nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin:malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands:neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.

[0229] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof andpharmaceutical compositions comprising such compounds and salts also may be coadministered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.

[0230] Also provided herein is a compound of Formula I, Formula I-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein for use in therapy.

[0231] Also provided herein is a compound of Formula I, Formula l-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.

[0232] Also provided herein is a compound of Formula I, Formula I-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof for use in the inhibition of KRas G12C.

[0233] Also provided herein is a compound of Formula I, Formula I-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a KRas G12C- associated disease or disorder.

[0234] Also provided herein is the use of a compound of Formula I, Formula I-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.

[0235] Also provided herein is a use of a compound of Formula I, Formula I-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvatethereof, as defined herein in the manufacture of a medicament for the inhibition of activity of KRas G12C.

[0236] Also provided herein is the use of a compound of Formula I, Formula I-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRas G12C-associated disease or disorder.

[0237] Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12C mutation (e.g., a KRas Gl2C-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula I-B, Formula II, Formula II-A or Formula II-B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0238] One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0239] One skilled in the art will further recognize that human clinical trials including first-in- human, dose ranging and efficacy trials, in healthy patients and / or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.REACTION SCHEMES AND EXAMPLES

[0240] The compounds of the present invention may be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those skilled in the art.

[0241] For instance, compounds of the present invention may be prepared according to the General Reaction Schemes I and II.GENERAL REACTION SCHEMESSCHEME I

[0242] Compounds of Formula I wherein L and Y are bonds, R2is hydrogen and R4is aryl or heteroaryl can be prepared according to Scheme I. In step A, an appropriately functionalized dihydropyridopyrimidine (1) is coupled to a heterocycle containing one nucleophilic amine species, with the other bound to a protecting group to provide compound (2). This coupling proceeds in a solvent such as dichloromethane in the presence of a base such as triethylamine or Hunig’s base. In step B, the Boc group of compound (2) is removed using conditions known in the art, for example with trifluoroacetic acid in a solvent such as dichloromethane, to provide compound (3). In step C, the substituent R4is introduced with a palladium coupling, using a suitable functionalized aryl or heteroaryl system, for example an aryl triflate, in the presence of a palladium catalyst such as Pd2DBA3 / Xantphos in a solvent such as toluene with a base such as sodium tert-butoxide to provide compound (4). In step D, the protecting group of ring X compound (4) is removed, for example hydrogenolysis by Pd / C in the presence of H2in a polar solvent such as EtOH / THF to provide compound (5). In the final step, E, R1is introduced to provide a compound of Formula I, for example by treating with an acid chloride having the formula C1-C(0)C(RA) C(RB)Por Cl-S02C(RA) — . C(RB)Por an anhydride having the formula C(RB)p^^= C(RA)C(0)0C(0)C(RA) C(RB)P, where RA, RBand p are as defined for Formula I. For example, in the case where R1is an acryloyl group, this reaction proceeds, for example, in a solvent such as methylene chloride in the presence of acryloyl chloride or an acryloyl anhydride and a base such as Hunig’s base. In some cases, the speciesR4will also contain a protecting group, which can be removed at a subsequent step in the synthetic sequence.

[0243] Compounds (1), (2), (3), (4) and (5) as shown and described above for Scheme I are useful as intermediates for preparing compounds of Formula I and are provided as further aspects of the invention.iSCHEME II

[0244] Compounds of Formula I wherein L is a bond, -Y-R2is other than hydrogen and R4is aryl or heteroaryl can be prepared according to Scheme II. In step A, an appropriately functionalized dihydropyridopyrimidine (6) is coupled to a heterocycle containing one nucleophilic amine species, with the other bound to a protecting group to provide compound (7). This coupling proceeds in a solvent such as dichloromethane in the presence of a base such as triethylamine or Hunig’s base. In step B, the substituent -Y-R2is introduced by substitution of the chlorine by a nucleophile, for example (S)-l -(dimethylamino-propan-2-ol in a polar solvent such as dioxane to provide compound (8). In step C, the Boc group is removed usingconditions known in the art, for example with trifluoroacetic acid in a solvent such as dichloromethane to provide compound (9). in step D, the substituent R4is introduced with a palladium coupling, using a suitable functionalized aryl or heteroaryl system, for example an aryl triflate, in the presence of a palladium catalyst such as Pd2DBA3 / BINAP in a solvent such as toluene with a base such as sodium tert-butoxide to provide compound (10). In step E, the protecting group of ring X is removed, for example hydrogenolysis by Pd / C in the presence of ¾ in a polar solvent such as EtOH / THF to provide compound (11). In step F, R1is introduced to provide a compound of Formula I, for example by treating with an acid chloride having the formula C1-C(0)C(RA) == C(RB)Por C1-S02C(RA) == C(RB)P,or an anhydride having the formula C(RB)P=== C(RA)C(0)0C(0)C(Ra) == C(RB)P, where RA, RBand p are as defined for Formula I. For example, in the case where R1is an acryloyl group, this reaction proceeds, for example, in a solvent such as methylene chloride in the presence of acryloyl chloride acryloyl anhydride and a base such as Hunig’s base. In some cases, the species R4and R2may also contain protecting groups, which can be removed at a subsequent step in the synthetic sequence.

[0245] Compounds (6), (7), (8), (9), (10) and (11) as shown and described above for Scheme 2 are useful as intermediates for preparing compounds of Formula I, Formula I-A or Formula I-B and are provided as further aspects of the invention.

[0246] Accordingly, also provide is a process for preparing a compound of Formula I, comprising:

[0247] (a) for a compound of Formula I where Y is a bond and R2is hydrogen, reacting a compound of formula 5

[0248] where X, R3and R4are as defined for Formula I, with an acid chloride having the formula ng theare as defined for Formula I, in the presence of a base; or

[0249] (b) for a compound of Formula I wherein L is a bond and -Y-R2is other than hydrogen, reacting a compound of formula (1 1)

[0250] wherein L is a bond, -Y-R2is other than hydrogen, and X, R3and R4are as defined for Formula I, with an acid chloride having the formula C1-C(0)C(Ra) = C(RB)Por Cl- S02C(Ra) = C(Rb)p, or an anhydride having the formula C(RB)p:=C(RA)C(0)0C(0)C(Ra) - .— C(Rb)Pwhere RA, RBand p are as defined for Formula I, in the presence of a base; and

[0251] optionally forming a salt thereof.

[0252] The compounds of the present invention may have one or more chiral center and may be synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures or the individual components / isomers may be separated using commercially available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK© (Sigma-Aldrich) or CFIIRALCEL® (Diacel Corp) chiral chromatographic HPTC columns according to the manufacturer’s instructions. Alternatively, compounds of the present invention may be synthesized using optically pure, chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of theinvention. Unless otherwise indicated, whenever the specification, including the claims, refers to compounds of the invention, the term“compound” is to be understood to encompass all chiral (enantiomeric and diastereomeric) and racemic forms.

[0253] The following Examples are intended to illustrate further certain embodiments of the invention and are not intended to limit the scope of the invention.Intermediate 13-(methoxymethoxy)naphthalen-l -yl trifluoromethanesulfonate

[0254] 3-Hydroxynaphthalen-l-yl trifluoromethanesulfonate (13.101 g, 44.831 mmol) was dissolved in dichloromethane (100 mL) and stirred at 0 °C. To this solution was added chloro(methoxy)methane (3.7456 ml, 49.315 mmol) and Hunig's base (11.745 mL, 67.247 mmol). The reaction was stirred at 0 °C for 4 hrs. The reaction was partitioned with 1M HC1 and washed with saturated sodium bicarbonate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The concentrated material was loaded onto a 120 g RediSep© gold silica gel column with dichloromethane and purified by normal phase chromatography (CombiFlash®, 0%-20% ethyl acetate / hexanes as the eluent) to give 3- (methoxymethoxy)naphthalen-l-yl trifluoromethanesulfonate (11.785 g, 35.045 mmol, 78.171 % yield).Intermediate 22-bromo-7-(methoxymethoxy)naphthalene

[0255] To a solution of 7-bromonaphthalen-2-ol (2.0 g, 9.0 mmol) in dimethyl acetamide (40 mL) was added chloro(methoxy)methane (1.4 g, 18 mmol) and cesium carbonate (5.8 g, 18 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction was diluted with water and the aqueous layer washed with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated under vacuum. The crude material was purified by normal phase chromatography using 5-50% ethyl acetate / hexanes as the eluent to give 2-bromo-7-(methoxymethoxy)naphthalene (1.0 g, 3.7 mmol, 42 % yield).Intermediate 32-bromo- 1 -fluoro-3 -(methoxymethyl)benzene

[0256] To a stirred solution of 2-bromo-3-fluorophenol (1422 mg, 7.445 mmol) in 22 mL tetrahydrofuran at room temperature under nitrogen was added NaH (327.6 mg, 8.190 mmol) neat as a solid portion wise. After 15 minutes, a solution had formed.Chloro(methoxy)methane (678.6 pL, 8.934 mmol) was added by syringe. After stirring for 2 hours, the reaction was quenched with saturated ammonium chloride solution and then partitioned between ethyl acetate (30 mL) and water (30 mL). The combined organic layers were isolated, washed with brine, dried over MgS04, filtered and concentrated. The crude product was loaded in a minimum of dichloromethane onto a 40 gram RediSep® column pre wet with hexanes and eluted with an ethyl acetate / hexanes gradient (0% to 20% ethyl acetate). Fractions containing the product were combined and concentrated to provide the product as a clear oil (1.45g, 83%).Intermediate 42-bromo- 1 -fluoro-4-(methoxymethoxy)benzene

[0257] To a stirred solution of 3-bromo-4-fluorophenol (327 mg, 1.71 mmol) in 5.1 mL tetrahydrofuran at room temperature under nitrogen was added NaH (75.3 mg, 1.88 mmol) neat as a solid portion wise. After 15 minutes, a solution had formed. Chloro(methoxy)methane (156 pL, 2.05 mmol) was added by syringe. After stirring for 2 hours, the reaction was quenched with saturated ammonium chloride solution and partitioned between ethyl acetate and water. The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated. The crude product was loaded in a minimum of dichloromethane onto a 24 gram RediSep® column pre-wet with hexanes and eluted with an ethyl acetate / hexanes gradient (0% to 20% ethyl acetate). Fractions containing the product were combined and concentrated to provide the product as a clear oil (120 mg, 29.8%)Intermediate 54-bromo-5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-l H-indazole

[0258] To a solution of 4-bromo-5-methyl-lH-indazole (0.7 g, 3.3 mmol) in dimethyl acetamide (30 mL) cooled to 0 °C was added NaH (0.19 g, 4.6 mmol) in portions and the reaction mixture was purged with nitrogen. The reaction was stirred for 20 minutes, and then (2- (chloromethoxy)ethyl)trimethylsilane (0.83 g, 5.0 mmol) was added and the reaction was stirred for 2 hours while warming to room temperature. The reaction was quenched by pouring into water and the aqueous layer was extracted into ethyl acetate. The combined organic layers were washed with water and brine, dried over MgS04and concentrated under vacuum. The crude material was purified by chromatography using 10-50% ethyl acetate / hexanes as the eluent to give 4-bromo-5-methyl-l -((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole (0.87 g, 79%).Intermediate 6(R)- 1 -(pyrrolidin- 1 -yl)propan-2-ol

[0259] In a sealed tube, R-(+)-Propylene oxide (3.69 mL, 52.7 mmol) was cooled to -78°C and then sparged with anhydrous dimethyl amine for a few minutes. The reaction mixture was heated to 70°C for 16 hours. The reaction was cooled and concentrated in vacuo for 20 minutes to provide (R)-l -(pyrrolidin- 1 -yl)propan-2-ol (5.35 g, 41.4 mmol, 98.2% yield).Intermediate 7(R)- 1 -morpholinopropan-2-ol

[0260] In a sealed tube, R-(+)-Propylene oxide (2.1 1 1 mL, 30.13 mmol) and morpholine (1 .490 mL, 17.22 mmol) were heated to 70°C for 20 hours. The reaction was cooled and concentrated in vacuo to provide (R)-l -morpholinopropan-2-ol (2.47 g, 17.01 mmol, 98.80 % yield).Intermediate 8(R)- 1 -(dimethylamino)butan-2-ol

[0261] In a sealed tube, R-(+)-Propylene oxide (4.00 g, 55.5 mmol) and dimethylamine (1.00 g, 22.2 mmol), were heated to 65°C for 18 hours. The reaction was cooled and concentrated in vacuo. The resulting residue was purified by silica gel (0-12% MeOH in DCM) to provide (R)- l-(dimethylamino)butan-2-ol (1.38 g, 1 1.8 mmol, 53.1 % yield).Intermediate 9(R)- 1 -((R)-3 -methoxypyrrolidin- 1 -yl)propan-2-ol

[0262] In a sealed tube, (R)-3-methoxypyrrolidine hydrochloride (1.00 g, 7.27 mmol), TEA (2.03 mL, 14.5 mmol) and R-(+)-Propylene oxide (1.27 mL, 18.2 mmol) were heated to 65°C for 18 hours. The reaction was cooled and concentrated in vacuo. The resulting residue was purified by silica gel (0-12% MeOH in DCM) to provide (R)-l-((R)-3 -methoxypyrrolidin- 1- yl)propan-2-ol (775 mg, 4.87 mmol, 67.0 % yield).Intermediate 10(R)- 1 -((S)-3-methoxypyrrolidin- 1 -yl)propan-2-ol

[0263] In a sealed tube, (S)-3-methoxypyrrolidine hydrochloride (1.00 g, 7.27 mmol), TEA (2.03 mL, 14.5 mmol) and R-(+)-Propylene oxide (1.27 mL, 18.2 mmol) were heated to 65°Cfor 18 hours. The reaction was cooled and concentrated in vacuo. The resulting residue was purified by silica gel (0-12% MeOH in DCM) to provide (R)-l-((S)-3-methoxypyiTolidin-l- yl)propan-2-ol (781 mg, 4.90 mmol, 67.5 % yield)Intermediate 11(R)-l-((S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-l-yl)propan-2-ol

[0264] In a sealed tube, R-(+)-Propylene oxide (0.609 mL, 8.69 mmol) and (S)-3-((tert- butyldimethylsilyl)oxy)pyrrolidine (1.00 g, 4.97 mmol) were heated to 70°C for 20 hours. The reaction was cooled and concentrated in vacuo to provide (R)-l-((S)-3-((tert- butyldimethylsilyl)oxy)pyrrolidin-l-yl)propan-2-ol (1.29 g, 4.20 mmol, 84.6 % yield).Intermediate 12Boctert-butyl 2-(hydroxymethyl)-4-methylpiperazine- 1 -carboxylate

[0265] To a suspension of lithium chloride (246 mg, 5.81 mmol) and Lithium Borohydride (126 mg, 5.81 mmol) in ethanol (9 mL), at 0°C under nitrogen, a solution of 1 -(tert-butyl) 2-methyl 4-methylpiperazine-l ,2-dicarboxylate (750 mg, 2.90 mmol) in dry THF (6 mL) was added dropwise. The reaction was stirred overnight forming a white precipitate. The precipitate was filtered and washed with ethanol. The combined filtrate and organic extracts were concentrated to provide a white residue which was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by chromatography with isocratic 10% MeOHin DCM with 0.2% NH4OH to provide tert-butyl 2-(hydroxymethyl)-4-methylpiperazine-l - carboxylate (104 mg, 0.452 mmol, 15.6 % yield).Intermediate 13(S)-2-(2-methylpiperidin- 1 -yl)ethan- 1 -ol

[0266] A mixture of (S)-2-methylpiperidine (100 mg, 1.01 mmol), 2-bromoethanol (78139 mg, 1.1 1 mmol, 1.1 eq.), sodium iodide (151 mg, 1 eq.), potassium carbonate (418 mg, 3 eq.) and acetonitrile (1 mL) in a 4-mL vial was purged with nitrogen, sealed and stirred at room temperature for 2 days. The reaction mixture was partitioned between diethyl ether (15 mL) and water (2 mL). The ether layer was washed with brine (2 mL), acidified with TFA and dried under high vacuum for 2 days. The residue was washed with ether (3 mL), diluted with water (0.5 mL) and basified with 10M NaOLl (0.2 mL). The layers were separated and the upper layer was carefully dried over NaOH. The ether solution was evaporated under nitrogen to yield crude (S)-2-(2-methylpiperidin-l-yl)ethan-l -ol (100 mg, 0.698 mmol, 69.24% yield) as colorless oil.Intermediate 14(R)-2-(2-methylpiperidin- 1 -yl)ethan- 1 -ol

[0267] Synthesized according to the method of Intermediate 13, using (R)-2-methylpiperidine (99 mg, 1 mmol) in place of (S)-2-methylpiperidine.Intermediate 15(S)-2-(3 -methoxypiperidin- 1 -yl)ethan- 1 -ol

[0268] Synthesized according to the method of Intermediate 13, using (S)-3-methoxypiperidine (173 mg, 1.50 mmol) in place of (S)-2-methylpiperidine.Intermediate 16(R)-2-(3 -methoxypiperidin- 1 -yl)ethan- 1 -ol

[0269] Synthesized according to the method of Intermediate 13, using R-3-methoxypiperidine (173 mg, 1.50 mmol) in place of (S)-2-methylpiperidine.Intermediate 173-( 1 ,4-oxazepan-4-yl)propan- 1 -ol

[0270] To a vial was added homomorpholine (0.250 g, 2.472 mmol), Acetonitrile (4.943 mL, 2.472 mmol) and 3 -Bromo-1 -propanol (0.2459 mL, 2.719 mmol). Potassium carbonate (0.6832 g, 4.943 mmol) was added and the mixture was warmed to 50 °C and stirred for 6 hours. The mixture was cooled to ambient temperature, diluted with DCM, filtered and the collected solids were washed with DCM. The filtrate was concentrated in vacuo and the crude oil was purifiedvia column chromatography (Biotage Isolera, 12g Isco RediSep Gold, 10-20% MeOH / DCM with 0.2% NH4OH) to afford 3-(l ,4-oxazepan-4-yl)propan-l -ol (0.272 g, 1.708 mmol) as a colorless oil.Intermediate 183 -(( 1 S ,4S)-2-oxa- 5 -azabicyclo [2.2.1 ]heptan-5 -yl)propan- 1 -ol

[0271] Synthesized according to the method of Intermediate 17, using (l S,4S)-2-Oxa-5- azabicyclo[2.2. l]heptane (0.250 g, 2.522 mmol) in place of homomorpholine.Intermediate 192-(4-methoxypiperidin-l -yl)ethan-l -ol

[0272] Synthesized according to the method of Intermediate 13, using 4-methoxypiperidine (173 mg, 1.50 mmol) in place of (S)-2-methylpiperidine.Intermediate 202-(4,4-difluoropiperidin- 1 -yl)ethan- 1 -ol

[0273] Synthesized according to the method of Intermediate 13, using 4,4-difluoropiperidine hydrochloride (173 mg, 1.50 mmol) in place of (S)-2-methylpiperidine.Intermediate 21(S)-2-(3-fluoropiperidin-l -yl)ethan-l -ol

[0274] Synthesized according to the method of Intermediate 13, using S-3-fluoropiperidine hydrochloride (209 mg, 1.50 mmol) in place of (S)-2-methylpiperidine.Intermediate 22Cbzbenzyl 4-(7-(3-(benzyloxy)naphthalen-l -yl)-2-(methylsulfmyl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazine- 1 -carboxylate

[0275] Step A: tert-butyl 4-hvdroxy-2-(methylthio )-5,8-dihydropyrido[3 4-dlpyrimidine-7 -carboxylate: To a stirred solution of 1 -tert-butyl 4-ethyl 3-oxopiperidine-l ,4-dicarboxylate (50.0 g, 184 mmol, 1.00 eq ) in MeOH (1.00 L) at 25 °C under nitrogen was added NaOMe (49.8 g, 921 mmol, 5.00 eq ), followed by 2-methylisothiourea (62.4 g, 331 mmol, 1.80 eq, H2SO4) as a solid. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was adjusted to pH 5 with HC1 (2 M), and the mixture was concentrated under reduced pressure to removed MeOH. The residue was suspended in 300 mL of ethyl acetate and 300 mL of water and stirred rapidly. The suspension was filtered and the white solid was collected. The filtrate was separated and the organic layer was washed with water (1c300 mL) and brine (1c200mL). The combined organic layers were isolated, dried over Na2S04, filtered and concentrated to provide tert- butyl 4-hydroxy-2-methylsulfanyl-6,8-dihydiO-57 / -pyrido[3,4-d]pyrimidine-7- carboxylate (51.0 g, 138 mmol, 75.4 % yield, 81.0 % purity) as a white solid which as used directly in the next step without further purification. ESI MS m / z 298.2 [M+H]+.

[0276] Step B: / er / -butyl 2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-pyndo[ 3.4-d lpyrimidinc-7-carboxylate: To a stirred suspension of tert- butyl 4-hydroxy-2- methylsulfanyl-6,8-dihydro-577-pyrido[3,4-d]pyrimidine-7-carboxylate (51.0 g, 171 mmol, 1.00 eq) in DCM (500 mL) at 0 °C was added DIEA (44.3 g, 343 mmol, 59.9 mL, 2.00 eq), followed by trifluoromethanesulfonic anhydride (72.6 g, 257 mmol, 42.4 mL, 1.50 eq) under nitrogen. Immediately a brown solution formed. After stirring at 25 °C for 16 hours, the reaction was concentrated to give a brown oil. The brown oil was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate = 1 :0 to 10:1) to provide / c / 7-bulyl 2-methylsulfanyl-4- (trifluoromethylsulfonyloxy)-6,8-dihydiO-5T / -pyrido[3,4-d]pyrimidine-7-carboxylate (46.0 g, 107 mmol, 62.4 % yield) as a yellow solid ESI MS m / z 430.2 [M+H]+.

[0277] Step C: tert- butyl 4-(4-benzyloxycarbonylpiperazin- 1 -yl)-2-methylsulfanyl-6,8-dihydro- 5 / / -pyrido[3.4-d]pyrimidine-7-carboxylate: To a stirred solution of tert- butyl 2-methylsulfanyl- 4- (trifluoromethylsulfonyloxy)-6,8-dihydro-5f: / -pyrido[3,4-d]pyrimidine-7-carboxylate (46.0 g, 107 mmol, 1.00 eq) in DMF (500 mL) was added DIEA (27.7 g, 214 mmol, 37.4 mL, 2.00 eq) followed by benzyl piperazine- 1 -carboxylate (25.9 g, 117 mmol, 22.7 mL, 1.10 eq). The reaction was heated to 100 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was poured into ethyl acetate (300 mL), washed with H20 (300 mL x 3) and brine (200 mL), dried over anhydrous Na2S04, filtered and concentrated under vacuum. The residue was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate = 1 :0 to 5:1) to give / e / 7 -butyl 4- (4-benzyloxycarbonylpiperazin- 1 -yl)-2-methylsulfanyl-6,8-dihydro-5 / / -pyrido [3 ,4- d]pyrimidine-7-carboxylate (51.0 g, 96.9 mmol, 90.5 % yield, 92.0 % purity) as a white solid ESI MS m / z 500.3 [M+H]+.

[0278] Step D: Benzyl 4-(2-methylsulfanyl-5 7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) piperazine- 1 -carboxylate: To a solution of tert- butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2- methylsulfanyl-6,8-dihydro-57 / -pyrido[3,4-d]pyrimidine-7-carboxylate (25.0 g, 50.0 mmol,1.00 eq) in DCM (50.0 mL) was added TFA (85.6 g, 750 mmol, 55.6 mL, 15.0 eq). Afterstirring at 25 °C for 1 hour, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 300 mL of ethyl acetate and 300 mL of water and stirred rapidly. The mixture was adjusted to pH 8 with Na2C03. The organic layer was washed with water (1c300 mL) and brine (1 x 200 mL), dried over Na2S04, filtered and concentrated under reduced pressure to provide benzyl 4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) piperazine- 1 -carboxylate (19.0 g, 46.6 mmol, 93.2 % yield, 98.0 % purity) as a yellow oil. ESI MS m / z 400.2 [M+H]+.

[0279] Step E : Benzyl 4-[7-(3-benzyloxy-l-naphthyl)-2-methylsulfanyl-6.8-dihydro-5 / 7- PVrido[3,4-d]pyrimidin-4-yl1piperazine-l -carboxylate: A mixture of 3-benzyloxy-l -bromo- naphthalene (16.3 g, 52.1 mmol, 1.30 eq ), benzyl 4-(2-methylsulfanyl-5,6,7,8- tetrahydropyrido [3, 4-d]pyrimidin-4-yl)piperazine-l -carboxylate (16.0 g, 40.1 mmol, 1.00 eq), Cs2C03(32.6 g, 100 mmol, 2.50 eq), Pd2(dba)3(5.50 g, 6.01 mmol, 0.15 eq) and 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (3.74 g, 8.01 mmol, 0.20 eq) in dioxane (300 mL) was degassed and purged with nitrogen 3 times. The mixture was stirred at 85 °C for 5 hours under a nitrogen atmosphere. The reaction mixture was quenched by adding water (200 mL) at 0 °C, and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si02,DCM / MeOH = 10 / 1 to 5 / 1) to provide benzyl 4-[7-(3-benzyloxy-l-naphthyl)-2-methylsulfanyl- 6,8-dihydro-5 / 7-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (16.0 g, 22.8 mmol, 56.9 % yield, 90.0 % purity) as a yellow solid. ESI MS m / z 632.5 [M+PI]+.

[0280] Step F: Benzyl 4-[7-(3-benzyloxy-l-naphthvD-2-methylsulfinyl-6.,8-dihydro- pyrido[3,4-dlpyrimidin-4-yl]piperazine-l -carboxylate :To a stirred solution of benzyl 4-[7-(3- benzyloxy-l-naphthyl)-2- methylsulfanyl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-4- yl]piperazine-l -carboxylate (8.00 g, 12.7 mmol, 1.00 eq) in DCM (200 mL) was added m- CPBA (2.73 g, 12.7 mmol, 80.0 % purity, 1.00 eq) at 0 °C under nitrogen. After stirring at 0 °C for 2 hours under a nitrogen atmosphere, the reaction mixture was quenched by adding Na2S203(10.0 mL) at 0 °C, diluted with water (100 mL) and extracted with DCM (200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by columnchromatography (S1O2, DCM / MeOH = 1 / 0 to 10 / 1) to provide benzyl 4-[7-(3-benzyloxy-l - naphthyl)-2-methylsulfmyl-6,8-dihydro-5 / / -pyrido [3,4-d]pyrimidin-4-yl]piperazine-l- carboxylate (3.50 g, 4.92 mmol, 38.8 % yield, 91.0 % purity) as a yellow solid. ESI MS m / z 648.5 [M+H]+.Intermediate 23(R)- 1 -(4-(2-hydroxypropyl)piperazin- 1 -yl)ethan- 1 -one

[0281] Step A: 1 - [4- [( -2-hvdroxyproryl1 piperazin- 1 -yl] ethanone : (2R)-2-methyloxirane(1.00 g, 17.2 mmol, 1.20 mL, 1.00 eq) and 1-piperazin-l -yl ethanone (8.00 g, 62.4 mmol, 3.62 eq) were taken up into a microwave tube. The sealed tube was heated at 150 °C for 1 hour under microwave. The mixture was dissolved in DCM (80.0 mL), added (Boc)20 (3.62 eq,13.6 g) and stirred at 20 °C for 1 hour. The residue was purified by column chromatography (DCM / MeOH 100 / 1 to 10 / 1) to give l -[4-[(2i?)-2-hydroxypropyl]piperazin-l -yl]ethanone (3.80 g, 13.5 mmol, 78.2 % yield, 66.0 % purity) as a yellow oil.Intermediate 24l -(benzyloxy)-3-bromo-5-cyclopropylbenzene

[0282] Step A: l -benzyloxy-3,5-dibromo-benzene: To a mixture of 3,5-dibromophenol (1.50 g, 5.95 mmol, 1.00 eq) and K2CO3(2.47 g, 17.9 mmol, 3.00 eq) in MeCN (30.0 mL) was added benzyl bromide (1.07 g, 6.25 mmol, 742 pL, 1.05 eq), the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered and concentrated. The residue was purified bycolumn chromatography (Si02, Petroleum ether / Ethyl acetate = 1 :1 to give l-benzyloxy-3,5- dibromobenzene (1.60 g, 4.68 mmol, 78.6 % yield) as colorless oil.

[0283] Step B: 1 -benzyloxy-3 -bromo-5 -cyclopropylbenzene : To a mixture of l-benzyloxy-3,5- dibromobenzene (1.20 g, 3.51 mmol, 1.00 eq) and cyclopropylboronic acid (392 mg, 4.56 mmol, 1.30 eg) in H20 (4.00 mL) and dioxane (20.0 mL) was added Pd(dppf)Cl2(513 mg, 702 pmol, 0.20 eg) and Cs2C03(2.29 g, 7.02 mmol, 2.00 eq). The reaction mixture was stirred at 90 °C for 12 hours under N2. The reaction mixture was added to water (20 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate = 1 :1 to give l-benzyloxy-3-bromo-5-cyclopropyl -benzene (270 mg, 890 pmol, 25.4 % yield) as colorless oil.Intermediate 25Cbzbenzyl 4-(2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-l- carboxylate

[0284] Step A: tert- butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2-(3-morpholinopropoxy)-6,8- dihvdro-577-pyrido[3,4-dlpyrimidine-7-carboxylate: To a mixture of 3-morpholinopropan-l-ol (5.46 g, 37.6 mmol, 2.00 eq) in THF (100 mL) was added NaH (2.26 g, 56.4 mmol, 60.0 % purity, 3.00 eq) in portions at 0 °C. After the mixture was stirred at 0 °C for 0.5 hour, a solution of / er -butyl 4-(4-benzyloxycarbonylpiperazin-l -yl)-2-methylsulfonyl-6,8-dihydro-5H- pyrido[3,4-d]pyrimidine-7-carboxylate (10.0 g, 18.8 mmol, 1.00 eq) in THF (100 mL) was added, and the reaction mixture was stirred at 0 °C for 1.5 hours under N2. The mixture was poured into NH4C1 aqueous (300 mL), and extracted with DCM (2c200 mL). The combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified bycolumn chromatography (Si02, Petroleum ether / Ethyl acetate=50: l to 10: 1) to give tert- butyl 4- (4-benzyloxycarbonylpiperazin-l-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5 / -pyrido[3,4- d]pyrimidine-7-carboxylate (7.70 g, 12.8 mmol, 67.8 % yield, 98.8 % purity) as a yellow oil. ESI MS m / z 597.4 [M+H]+.

[0285] Step B: benzyl 4- [2-(3 -morpholinopropoxy)-5 ,6,7, 8-tetrahydrop yrido f 3 ,4-d]pyrimidin-4- yllpiperazine-l -carboxylate: To a mixture of / er / -butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)- 2-(3-morpholinopropoxy)-6,8-dihydro-57 / -pyrido[3,4-d]pyrimidine-7-carboxylate (7.70 g, 12.9 mmol, 1.00 eq) in DCM (80.0 mL) was added TFA (1 19 g, 1.04 mol, 76.9 mL, 80.6 eq), and the reaction mixture was stirred at 15 °C for 1 hour. The reaction mixture was concentrated, then diluted with DCM (100 mL) and adjusted to pH 8 with aqueous NaOH. The organic layer was separated, dried over Na2S04, filtered and concentrated to give benzyl 4-[2-(3- morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l -carboxylate (6.00 g, 11.2 mmol, 86.9 % yield, 92.8 % purity) as yellow oil. ESI MS m / z 497.4 [M+H]+.Intermediate 264-(benzyloxy)-2-bromo- 1 -fluorobenzene

[0286] To a solution of 3-bromo-4-fluorophenol (4.00 g, 20.9 mmol, 1.00 eq) and K2CO3(8.68 g, 62.8 mmol, 3.00 eq) in ACN (80.0 mL) was added benzyl bromide (3.65 g, 21.4 mmol, 2.54 mL, 1.02 eq) and the reaction mixture was stirred at 60 °C for 2 hrs. The reaction mixture was filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum etherethyl acetate; gradient from 1 :0 to 10: 1) to give 4-benzyloxy-2-bromo-l- fluoro-benzene (5.02 g, 17.0 mmol, 81.0 % yield, 95 % purity) was obtained as white solid.Intermediate 272-(3-fluoiOpyrrolidin- 1 -yl)ethan- 1 -ol

[0287] Step A: butyl 3 -fluoro pyrrolidine- 1 -carboxylate: To a solution of / erf-butyl 3- hydroxypyrrolidine-l-carboxylate (10.0 g, 53.4 mmol, 1.00 eq) in DCM (150.00 mL) was added diethylaminosulfur trifluoride (DAST) (12.9 g, 80.1 mmol, 10.6 mL, 1.50 eq) at -40 °C under a nitrogen atmosphere. After stirring at - 40 °C for 2 hours, the mixture was warmed to 20 °C and stirred for 16 hours. The mixture was poured into 5% aqueous sodium bicarbonate (200 mL) and extracted with dichloromethane (2 x 100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (petroleum ether / ethyl acetate 100: 1 to 5:1). The desired fractions were collected and concentrated under vacuum to give / e / V-butyl 3-fluoropyrrolidine- 1 -carboxylate (4.30 g, 22.7 mmol, 42.6 % yield) as a colorless oil.!H NMR (400 MHz, Chloroform-d) d = 5.27 (t, J= 3.6 Hz, 0.5H), 5.13 (t, J = 3.6 Hz, 0.5H), 3.77 - 3.38 (m, 4H),2.26 - 2.15 (m, 1H), 2.08 - 1.85 (m, 1H), 1.46 (s, 9H).

[0288] Step B: 3 -fluoropyrrolidine : To a solution of / erf-butyl 3-fluoiOpyrrolidine-l -carboxylate (4.30 g, 22.7 mmol, 1.00 eq) in DCM (50.00 mL) was added HCl / dioxane (4 M, 35.0 mL, 6.16 eq) dropwise at 0 °C. The mixture was warmed to 20 °C and stirred for 1 hour. The mixture was concentrated under vacuum. The residue was triturated with diisopropyl ether (20 mL) and the precipitate was filtered and dried under vacuum to provide 3 -fluoropyrrolidine (2.70 g, 21.5 mmol, 94.6 % yield, HC1) as a white solid. 'Ll NMR (400 MHz, Methanol-d4) d = 5.51 (t, J = 3.6 Hz, 0.5H), 5.38 (t, J=3.6 Hz, 1H), 3.66 - 3.27 (m, 5H), 2.45 - 2.12 (m, 2H).

[0289] Step C: methyl 2-f3-fhioropyrrolidin-l -vPacetate: A suspension of 3 -fluoropyrrolidine (2.70 g, 21.5 mmol, 1.00 eq, HC1) in DCM (27.00 mL) was cooled to 0° C. Triethylamine (5.44 g, 53.8 mmol, 7.45 mL, 2.50 eq) and methyl 2-bromoacetate (3.62 g, 23.7 mmol, 2.23 mL, 3.10 eq) were added and the reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with CH2CI2 (100 mL) and water (50 mL). The organic layer was washed with 5% aqueous citric acid solution (1 x 50 mL). The water layer was basified by saturated aqueous sodium carbonate solution (20 mL) and extracted with ethyl acetate (3c100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give methyl 2-(3-fluoropyrrolidin-l -yl)acetate (2.20 g, 13.7 mmol, 63.5 % yield).’H NMR (400MHz, Chloroform-d) d = 5.22 - 5.02 (m, 1H), 3.66 (s, 3H), 3.35 (s, 2H), 3.07 - 2.93 (m, 1H), 2.91 - 2.77 (m, 2H), 2.67 (dt, J= 5.2, 8.4 Hz, 1H), 2.21 - 1.93 (m, 2H).

[0290] Step D: 2-(3-fluoropyrrolidin- 1 -vDethanol: To a solution of LiAlLL (706 mg, 18.6 mmol, 1.50 eq) in THF (20 mL) was added a solution of methyl 2-(3-fluoropyrrolidin-l-yl)acetate (2.00 g, 12.4 mmol, 1.00 eq) in THF (10 mL) dropwise at 0 °C. The mixture was warmed up to 20 °C and stirred for 3 hours. The mixture was quenched with saturated aqueous sodium sulfate solution (1 mL). The mixture was filtered and the filtrate was concentrated under vacuum. The product was purified by silica gel chromatography using 5% MeOH in DMC. The desired fractions were collected and concentrated under vacuum to give 2-(3-fluoropyrrolidin-l- yl)ethanol (1.20 g, 9.01 mmol, 72.6 % yield) as a colorless oil.NMR (400 MHz,Chloroform-d) d = 5.28 - 5.05 (m, 1H), 3.68 - 3.61 (m, 2FI), 2.99 - 2.73 (m, 4FI), 2.72 - 2.67 (m, 2H), 2.58 - 2.45 (m, 1H), 2.28 - 1.97 (m, 2H).Intermediate 281 -(tert-butyl) 3-methyl piperazine- 1 , 3 -dicarboxylate

[0291] Step A: methyl piperazine-2-carboxylate·. To a mixture of 1 -tert-butyl 2-methyl piperazine- 1 ,2-dicarboxylate (5.0 g, 22.6 mmol, 1.00 eq) in MeOH (50.0 mL) was added LlCl / dioxane (4.0 M, 134 mL). The reaction mixture was degassed and purged with nitrogen 3 times, and the mixture was stirred at 25 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to dryness to give methyl piperazine- 2-carboxylate (4.89 g, 2HC1, crude) as a white solid, which was used directly in the next step without further purification.

[0292] Step B: 1 -(tert-butyl) 3-methyl piperazine- L3-dicarboxylate: To a solution of methyl piperazine-2-carboxylate (4.30 g, crude) and TEA (8.02 g, 79.2 mmol, 1 1.0 mL) in MeOH (50.0mL) was added di-tert-butyl dicarbonate (4.32 g, 19.8 mmol, 4.55 mL). After stirring at 25 °C for 12 hours, the reaction mixture was filtered and concentrated under reduced pressure to dryness. The residue was purified by column chromatography (Si02, DCM / MeOH = 1 :0 to 20:1) to give 1 -(tert-butyl) 3-methyl piperazine- 1, 3 -dicarboxylate (4.80 g, 19.7 mmol, two steps, 99.0 % yield) as a colorless oil.'H NMR (400 MHz, chloroform-d) 5 = 4.10 - 3.85 (m, 1H), 3.73 (s, 3H), 3.71 - 3.65 (m, 1H), 3.47 - 3.38 (m, 1H), 3.10 - 2.98 (m, 2H), 2.78 - 2.66 (m, 1H), 2.17 (s, 1H), 1.46 (s, 9H).Intermediate 294-bromonaphthalen-2-ol

[0293] Step A: 2.9-dibromonaphthalen- 1 -amine: To a solution of Br2(246 g, 1.54 mol, 79.3 mL, 2.18 eq ) in AcOH (750 mL) was added a solution of naphthalen- 1 -amine (101 g, 705 mmol,99.0 mL, 1.00 eq) in AcOH (500 mL) at ambient temperature, and the reaction was stirred at 70 °C for 1 hour. The reaction mixture was cooled at room temperature and filtered. The filter cake was washed with AcOH (300 mL), then added to 20 % aqueous of NaOH (1.2 L). The mixture was stirred for 20 min and filtered. The isolated solid was washed with water (1 L) and dried under vacuum to provide 2,4-dibromonaphthalen-l -amine (200 g, 664 mmol, 94.2% yield) as gray solid. ESI MS m / z 301. 9 [M+H]+.

[0294] Step B: 4-bromo-l-diazonio-naphthalen-2-olate: To a solution of 2,4-dibromonaphthalen- l -amine (60.0 g, 199 mmol, 1.00 eq) in AcOH (900 mL) and propionic acid (150 mL) was added NaN02(16.5 g, 239 mmol, 13.0 mL, 1.20 eq) portionwise at 5-8 °C over 30 min, and then the reaction mixture was stirred at 5-8 °C for 30 min. The reaction mixture was poured into ice-water (4000 mL), and the resulting solid was collected and washed with water (2 x 50 mL) to provide 4-bromo-l-diazonio-naphthalen-2-olate (150 g, wet crude) as gray solid which was used directly in the next step. Ή NMR (400 MHz, CDCL) d 8.12 - 8.10 (d, J=8.4 Hz, 1H), 7.62- 7.58 (t, 7=7.6 Hz, 1H), 7.41 - 7.37 (t, .7=7 6 Hz, 1H), 7.31 - 7.29 (d, 7=8.0 Hz, 1H), 7.20 (s,1 H).

[0295] Step C: 4-bromonaphthalen-2-ol: To a solution of 4-bromo-l-diazonio-naphthalen-2- olate (100 g, 402 mmol, 1.00 eq ) in EtOH (2.00 L) was added portionwise NaBH4(30.4 g, 803 mmol, 2.00 eq) at 13-15 °C over 1 h, and the reaction mixture was stirred at 15-18 °C for 3 hrs. The reaction was filtered and concentrated to dryness. The residue was dissolved in DCM (1000 mL) and washed with water (500 mL x 2). The organic phase was dried over Na2S04and concentrated to dryness. The residue was purified by silica gel column chromatograph, eluting with diethyl ether / ethyl acetate (60:1 to 10:1). The isolated product was further purified by reversed phase HPLC to provide 4-bromonaphthalen-2-ol (40.0 g, 139 mmol, 17.3 % yield, 77.4% purity) as a gray solid. Ή NMR (400 MHz, CDC13) 8 8.07 - 8.05 (d, .7=8.0 Hz, 1H), 7.60 - 7.58 (d, ,7=7.6 Hz, 1H), 7.41 - 7.36 (m, 3H), 7.07 (s, 1H).

[0296] Step D: 3 -benzyloxy- 1 -bromo-naphthalene : A mixture of 4-bromonaphthalen-2-ol (30.0 g, 134 mmol, 1.00 eq), benzyl bromide (25.3 g, 148 mmol, 17.6 mL, 1.10 eq) and K2CO3 (55.7 g, 403 mmol, 3.00 eq) in MeCN (500 mL) was heated at 80 °C for 1 hr. The reaction mixture was filtered and concentrated to dryness. The residue was purified by silica gel column chromatography, eluting with diethyl ether / ethyl acetate (100:1 to 60:1) to provide 3-benzyloxy- 1 -bromo-naphthalene (40.0 g, 128 mmol, 95 % yield) as yellow oil. 'H NMR (400 MHz,CDCI3) d 8.19 - 8.17 (d, 7=8.0 Hz, 1H), 7.75 - 7.32 (d, 7=8.8 Hz, 1H), 7.64 - 7.63 (d, 7=2.4 Hz,IH), 7.52 - 7.37 (m, 7LI), 7.23 - 7.21 (d, 7=2.0 Hz,IH), 5.2 (s, 2H).Intermediate 303-methoxynaphthalen-l -yl trifluoromethanesulfonate

[0297] Step A: 3-methoxynaphthalen-l -ol : To a solution of naphthalene- 1 ,3-diol (3.00 g, 18.7 mmol, 1.00 eq) in MeOH (60.0 mL) was added HCl / MeOH (4 M, 60.0 mL, 12.8 eq) at 0 °C.The mixture was stirred at 25 °C for 60 hours. The solvent was removed under vacuum. Theresidue was purified by silica gel chromatography (diethyl ethenethyl acetate=10:l to 5:1) to give 3-methoxynaphthalen-l-ol (2.10 g, 12.1 mmol, 64.4% yield) as a brown solid. 'H NMR (400 MHz, CDCl3-d6) 6 = 8.10 - 8.08 (d, =8.4 Hz, lH).7.73 - 7.71 (d, J=8.4 Hz, 1H), 7.47 - 7.45(m, 1H), 7.38 - 7.35(m, 1H), 6.80 - 6.79 (d, =2.0 Hz, 1H), 6.56 - 6.55 (d, =2.4 Hz, 1H), 3.92 (s, 3H).

[0298] Step B: (3 -methoxy-l -naphthyl) trifluoromethanesulfonate: To a solution of 3- methoxynaphthalen-l-ol (2.10 g, 12.0 mmol, 1.00 eq) in DCM (40.0 mL) was added DIEA (7.79 g, 60.3 mmol, 10.5 mL, 5.00 eq) and trifluoromethanesulfonic anhydride (5.10 g, 18.1 mmol, 2.98 mL, 1.50 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was diluted with DCM (30 mL) and water (10 mL) and extracted with DCM (20 mL). The combined organic layers were washed with brine (5 mL), dried over Na2S04and concentrated under vacuum. The residue was purified by silica gel chromatography (diethyl ethenethylacetate=20: l to 10 :l) to give (3 -methoxy-l -naphthyl) trifluoromethanesulfonate (3.00 g, 8.52 mmol, 70.7 % yield, 87.0 % purity) as a brown oil. ESI MS m / z 307.1 [M+H]+.Intermediate 317-benzyl-2,4-dichloiO-6,8-dihydiO-577-pyrido[3,4-d]pyrimidine

[0299] Step A: 7-benzyl-6,8-dihydiO-5H-pyrido[3,4-d]pyrimidine-2,4-diol: To EtOH (600 mL) was added Na (5.56 g, 241 mmol, 5.73 mL, 2.40 eq) in portions. The reaction mixture was stirred for 1 hour. To the mixture was added ethyl 1 -benzyl-3 -oxo-piperidine-4-carboxylate (30.0 g, 100 mmol, 1.00 eq, HC1) and urea (14.5 g, 242 mmol, 13.0 mL, 2.40 eq). The reaction mixture was stirred at 75 °C for 36 hours, and then the solvent was removed under vacuum. The residue was dissolved in water (50 mL) and acidified with HC1 (120 mL, 2M). A white solid precipitated from the solution and was collected by filtration. The filter cake was dried under vacuum to provide 7-benzyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (22.0 g, 83.8 mmol, 83.2 % yield, 98 % purity) as a white solid. 'HNMR (400 MHz, DMSO-d6) d = 10.97 (brs, 1 H), 10.66 (br s, 1H), 7.55 - 6.95 (m, 5H), 3.81 - 3.50 (m, 2H), 3.26 - 2.91 (m, 2H), 2.77 - 2.58 (m, 2H), 2.34 - 2.09 (m, 2H).

[0300] Step B: 7-benzyl-2,4-dichloro-6,8-dihyd O--5 / 7-pyrido rimidine: To a solution ofDIEA (30.1 g, 233 mmol, 40.7 mL, 3.00 eq) in POCl3(330 g, 2.15 mol, 200 mL) was added 7- benzyl-6,8-dihydro-577-pyrido[3,4-d]pyrimidine-2,4-diol (20.0 g, 77.7 mmol, 1.00 eq). The reaction mixture was stirred at 110 °C for 5 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (400 mL) and poured into saturated NaHC03(200 mL). The mixture was extracted with DCM (2c400 mL). The combined organic layers were washed with brine (100 mL), dried over Na2S04and concentrated under vacuum. The residue was purified by silica gel chromatography (diethyl ether: DCM=10: l to 0: 1) to give 7-benzyl- 2,4-dichloro-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidine (7.70 g, 26.2 mmol, 33.7 % yield) as a brown oil.‘HNMR (300 MHz, chloroform-d) d = 7.43 - 7.28 (m, 5H), 3.73 (s, 2H), 3.66 (br s, 2H), 2.84 (br s, 4H)Intermediate 32te / 7-butyl4-(4-((benzyloxy)carbonyl)piperazin-l -yl)-2-(methylsulfonyl)-5,6-dihydropyrido[3,4- d]pyrimidine-7(877)-carboxylate

[0301] Step A butyl4-hvdroxy-2-methylsulfanyl-6,8-dihvdro-5H-pyrido[3,4-d]pyrimidine- 7-carboxylate: To a stirred solution of l- / e / 7-butyl 4-ethyl-3-oxopiperidine-l ,4-dicarboxylate (44.0 g, 162 mmol, 1.00 eq) in MeOH (1.00 mL) at 25 °C under nitrogen was added a solution ofNaOMe (35.0 g, 649 mmol, 4.00 eq) in MeOH (600 mL) by syringe followed by 2- methylisothiourea (61.1 g, 324 mmol, 2.00 eq, H2SO4). After stirring at 25 °C for 16 hours, thereaction mixture was concentrated under reduced pressure to removed MeOH. The residue was suspended in 500 mL of ethyl acetate and 500 mL of water and stirred rapidly. The reaction mixture was adjusted to pH 5 with HC1 (2 M). The precipitate was filtered and the white solid was washed with ethyl acetate and dried under vacuum to give tert- butyl4-hydroxy-2- methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (33.0 g, 103 mmol, 63.8 % yield, 93.2 % purity) as a white solid, which was used directly in the next step without further purification. *H NMR (400 MHz, DMSO-d6) d = 4.19 (s, 2 H), 3.49 (br s, 2 H), 2.46 (s, 3 H), 2.35 (br X, J— 5.2 Hz, 2 H), 1.42 (s, 9 H).

[0302] Step B: give / gr / -butyl 2-methylsulfauyl-4-(tnfhioromethylsulfonyloxy)-6.8-dihydro-pyrido [3,4-d]pyrimidine-7-carboxylate: To a stirred suspension of to-t-butyl 4-hydroxy-2- methylsulfanyl -6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (15.0 g, 50.4 mmol,1.00 eq) in DCM (200 mL) was added DIEA (26.1 g, 202 mmol, 35.2 mL, 4.00 eq ) at 0 °C under nitrogen and followed by trifluoromethanesulfonic anhydride (28.5 g, 101 mmol, 16.6 mL, 2.00 eq) by syringe. Immediately a brown solution formed. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate = 1 :0 to 10: 1) to give / er / -butyl 2-methylsulfanyl-4- (trifluoromethylsulfonyloxy)-6,8-dihydro-5 / 7-pyrido [3,4-d]pyrimidine-7-carboxylate (16.7 g, 35.7 mmol, 70.9 % yield, 91.9 % purity) as a white solid. ESI MS m / z 374.0 [M+H]+.

[0303] Step C butyl 4-(4-benzyloxycarbonylpiperazin- 1 -yl)-2-methylsulfanyl-6,8- dihydro- 5H-pyrido [ 3 ,4-d]pyrimidine-7-carboxylate : To a stirred solution of / er / -butyl2-methylsiilfanyl- 4-(trifluoromethyl sulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (16.7 g, 38.9 mmol, 1.00 eq) in DMF (100 mL) was added DIEA (10.0 g, 77.9 mmol, 2.00 eq) and benzyl piperazine- 1 -carboxyl ate (9.41 g, 42.8 mmol, 1.10 eq). The reaction was heated to 100 °C and stirred for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted with water (150 mL) and the reaction mixture was adjusted to pH 5 with HC1 (2 M) and extracted with DCM (3x 200 mL). The combined organic layers were washed with saturated NaHC03(3 x 150 mL), brine (3 x 150 mL) and H20 (3 x 150 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give te- / -butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)- 2-methylsulfanyl-6,8- dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (18.1 g, 36.2 mmol,93.0 % yield, 94.1 % purity) as a yellow solid, which was used directly in the next step without further purification. ESI MS m / z 500.1 [M+H]+.

[0304] Step D: tert-butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2- methylsulfonyl-6,8-dihydro- 5H-pyridor3,4-dlpyrimidine-7-carboxylate: To a stirred solution of tert-butyl4-(4- benzyloxycarbonylpiperazin -l-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine- 7-carboxylate (14.4 g, 28.9 mmol, 1.00 eq) in DCM (150 mL) at 0 °C under nitrogen was added meta-chloroperoxybenzoic acid (17.4 g, 101 mmol, 3.50 eq) as a solid. After stirring at 0 °C for 2 hours under a nitrogen atmosphere, the reaction mixture was diluted with water (300 mL) and the reaction mixture was adjusted to pH 8 with saturated aqueous NaHC03and extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over Na2S04, filtered and concentrated under reduced pressure to dryness. The residue was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate = 10: 1 to 1 :2) to give tert-butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyrido[3,4- d]pyrimidine-7-carboxylate (1 1.0 g, 19.7 mmol, 68.6 % yield, 95.4 % purity) as a white solid. ESI MS m / z 532.1 [M+H]+.Intermediate 33tert-butyl (1 -bromoisoquinolin-3-yl)carbamate

[0305] Step A: A mixture of l -bromoisoquinolin-3-amine (400 mg, 1.79 mmol, 1.00 eq) and / erZ-butoxycarbonyl tert-butyl carbonate (3.91 g, 17.9 mmol, 4.12 mL, 10.0 eq) was stirred at 70 °C for 16 hours. The residue was purified by column chromatography (Si02, diethyl ether / ethyl acetate = 5: 1) to give tert-butyl N-(l-bromo-3-isoquinolyl) carbamate (400 mg, 1.24 mmol, 69.2 % yield) as a yellow solid. ESI MS m / z 322.1 , 324.1 [M+H]+.Intermediate 343-methoxy-6-methylnaphthalen- 1 -yl trifluoromethanesulfonate

[0306] Step A: 3 -methoxynaphthalen- 1 -ol : To a solution of naphthalene-l,3-diol (40.0 g, 250 mmol, 1.00 eq) in MeOH (800 mL) was added HC1 (4 M, 750 mL, 12.0 eq, 4 M in MeOH) at 0 °C. The mixture was warmed up to 18 °C and stirred for 30 hours. The mixture wasconcentrated under vacuum. The residue was purified by column chromatography over silica gel (petroleum ether / ethyl acetate 100 / 1 to 1 / 1). The desired fractions were collected andconcentrated under vacuum to give 3 -methoxynaphthalen- l-ol (17.7 g, 96.5 mmol, 38.6 % yield, 95 % purity) as a red oil. 'H NMR (400MHz, Chloroform-d) 8 = 8.17 (d, J = 8.4 Hz, 1H), 7.74 (d, 7 = 8.0 Hz, 1H), 7.50 (ddd, 7= 1.2, 6.8, 8.0 Hz, 1H), 7.38 (ddd, 7=1.2, 6.8, 8.0 Hz, 1H), 6.81 (d, 7=2.0 Hz, 1H), 6.76 (br s, 1H), 6.62 (d, 7=2.4 Hz, 1H), 3.91 (s, 3H).

[0307] Step B: fer -butyl- [ ( 3 -methoxy- 1 -naphthvBoxyl -dimethyl-silane : To a solution of 3- methoxynaphthalen-l-ol (20.0 g, 1 15 mmol, 1.00 eq) and imidazole (23.5 g, 344 mmol, 3.00 eq) in THF (400 mL) was added TBSC1 (26.0 g, 172 mmol, 21.1 mL, 1.50 eq) dropwise at 0 °C.The mixture was warmed up to 25 °C and stirred for 16 hours. The mixture was diluted with petroleum ether (600 mL) and ethyl acetate (200 mL), and then washed with water (1 x 200 mL) and brine (1 x 200 mL). The separated organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (petroleum ether / ethyl acetate 100 / 1 to 10 / 1). / ert-butyl- [(3 -methoxy- l -naphthyl)oxy]- dimethyl-silane (28.0 g, 97.1 mmol, 84.6 % yield) was obtained as a colorless oil. 'H NMR (400MHz, Chloroform-d) d = 8.01 (d, .7= 8.4 Hz, 1H), 7.61 (d, 7 = 8.0 Hz, 1H), 7.35 (dt, . / =1.2, 7.6 Hz, 1H), 7.24 (dt, 7 = 1.2, 7.6 Hz, lH), 6.71 (d, 7= 2.0 Hz, 1 H), 6.48 (d, 7 = 2.4 Hz,HI), 3.82 (s, 3H), 1.02 (s, 9H), 0.23 (s, 6H).

[0308] Step C butyl-[[3-methoxy-6-(4,4.5.5-tetramethyl-L3.2-dioxaborolan-2-yl)-l - naphthyl]oxy]-dimethyl-silane and fcr / -butyl((3-methoxy-7-(4A5,5-tetramethyl- 1 ,3,2- dioxaboiOlan-2-yl)naphthalen- 1 -yl)oxy)dimethylsilane: A mixture of / <?r / -butyl-[(3-methoxy-l -naphthyl) oxy]-dimethyl-silane (26.0 g, 90.1 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (45.8 g, 180 mmol, 2.00 eq), (1Z,5Z)- cycloocta-l,5-diene;2,4-dimethyl-BLAHbicyclo[1.1.0]butane (2.39 g, 3.61 mmol, 0.04 eq) and 4- / <?r / -butyl-2-(4- / er -butyl-2-pyridyl)pyridine (1.45 g, 5.41 mmol, 0.06 eq) in hexane (500 mL) was stirred at 100 °C under nitrogen atmosphere for 16 hours. The mixture was diluted with water (500 mL) and ethyl acetate (1000 mL). The separated organic layer was washed with brine (1 x 500 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (petroleum etehr / ethyl acetate 100 / 1 to 10 / 1). The desired fractions were collected and concentrated under vacuum to give a mixture of teri-butyl-[[3-methoxy-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- naphthyl]oxy]-dimethyl-silane and ier / -butyl((3-methoxy-7-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)naphthalen-l-yl)oxy)dimethylsilane (38.0 g, 85.3 mmol, 94.6 % yield, 93 % purity) as a light yellow oil. ESI MS m / z 415.5 [M+H]+

[0309] Step D: 8-[7er / -biityl(dimetbyl)sily]]oxy-6-methoxy- naphthalen-2-oh To a solution of mixture (36.0 g, 86.9 mmol, 1.00 eq) of / <?r / -butyl-[[3-methoxy-6-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan-2-yl)-l- naphthyl]oxy]-dimethyl-silane and / cr / -butyl((3-methoxy-7-(4, 4,5,5- tetramethyl-1,3, 2-dioxaborolan-2-yl)naphthalen-l-yl)oxy)dimethylsilanein in acetone (400 mL) was added a solution of Oxone (58.7 g, 95.6 mmol, 1.10 eq) in H20 (400 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was quenched with 5% aqueous sodium thiosulfate solution (50 mL) and extracted with ethyl acetate (2 x 300 mL). The extracts were combined and washed with water (1c200 mL), brine (1 x 200 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography over silica gel (petroleum ether / ethyl acetate 200 / 1 to 20 / 1). The desired fractions were collected and concentrated under vacuum to give 8 -[tert- butyl(dimethyl)silyl]oxy-6-methoxy- naphthalen-2-ol (9.00 g, 28.4 mmol, 32.7 % yield, 96 % purity) as a colorless oil and 5-[ / er / -butyl(dimethyl)silyl]oxy-7-methoxy-naphthalen-2-ol (9.00 g, 29.0 mmol, 33.4 % yield, 98 % purity) as a white solid. ESI MS m / z 305.2 [M+H]+

[0310] Step E: [5-l / er / -butyl(dimethyl)silyl1oxy-7-methoxy-2 -naphthyl]trifluoromethanesulfonate: To a solution of 5-[ / er / -butyl(dimethyl)silyl]oxy-7- methoxy- naphthalen-2-ol (1 1.0 g, 36.1 mmol, 1.00 eq) and DIEA (14.0 g, 108 mmol, 18.9 mL, 3.00 eq)in DCM (150 mL) was added Tf20 (12.2 g, 43.4 mmol, 7.15 mL, 1.20 eq ) dropwise at - 40 °C. The mixture was stirred for 1 hour. The mixture was diluted with dichloromethane (200 mL) and washed with water (1 x 200 mL) and brine (1 x 200 mL). The separated organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (petroleum ether / ethyl acetate 100 / 1 to 10 / 1). The desired fractions were collected and concentrated under vacuum to give [5 -[tert- butyl(dimethyl)silyl]oxy-7-methoxy-2-naphthyl] trifluoromethanesulfonate (13.0 g, 29.8 mmol,82.4 % yield, 100 % purity) as a white solid. ESI MS m / z 436.9 [M+H]+

[0311] Step F butyl-r(3-methoxy-6-methyl-l-naphthyl)oxy1-dimethyl-silane: To a solution of [5-[ / er / -butyl(dimethyl)silyl]oxy-7-methoxy-2- naphthyl] trill uoromethanesulfonate (12.5 g, 28.6 mmol, 1.00 eq) and K2CO3 (1 1.9 g, 85.9 mmol, 3.00 eq) in dioxane (160 mL) was added Pd(PPh3)4 (3.31 g, 2.86 mmol, 0.10 eq) and trimethylboroxine (14.4 g, 57.3 mmol, 16.0 mL,2.00 eq) under nitrogen atmosphere. The reaction was heated to 100 °C for 16 hours. The mixture was diluted with ethyl acetate (200 mL) and then washed with water (1 x 200 mL) and brine (1 x 200 mL). The separated organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (petroleum ether / ethyl acetate 100 / 1 to 5 / 1). The desired fractions were collected and concentrated under vacuum to give / er / -buty]-[(3-methoxy-6-mcthyl-l -naphthy l)oxy] -dimethyl - silane (8.00 g, 24.6 mmol, 85.9 % yield, 93 % purity) as a colorless oil as red solid. ESI MS m / z 303.2 [M+H]+

[0312] Step G: 3-methoxy-6-methyl-naphthalen-l-ol: To a solution of / er / -butyl-[(3-methoxy-6- methyl-1 -naphthyl) oxy]-dimethyl-silane (8.00 g, 26.5 mmol, 1.00 eq) in THF (100 mL) was added TBAF (10.4 g, 39.7 mmol, 1.50 eq) at 0 °C. The mixture was stirred at 0 °C for 3 hours. The mixture was diluted with water (100 mL) and ethyl acetate (200 mL). The separated organic layer was washed with brine (1 x 100 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (petroleum ether / ethyl acetate 50 / 1 to 5 / 1). The desired fractions were collected andconcentrated under vacuum to give 3-methoxy-6-methyl-naphthalen-l-ol (4.70 g, 25.0 mmol,94.4 % yield) as a red solid. ESI MS m / z 188.4 [M+H]+

[0313] Step H: 3 -methoxy-6-methyl- 1 -naphthyl trifluoromethanesulfonate : To a solution of 3- methoxy-6-methyl-naphthalen-l-ol (4.70 g, 25.0 mmol, 1.00 eq) and DIEA (9.68 g, 74.9 mmol, 13.1 mL, 3.00 eq) in DCM (3.00 mL) was added Tf20 (8.45 g, 30.0 mmol, 4.94 mL, 1.20 eq) dropwise at - 40 °C. The mixture was stirred for 1 hour. The mixture was diluted with dichloromethane (200 mL) and washed with water (1 x 200 mL) and brine (1 x 200 mL). The separated organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (petroleum ether / ethyl acetate 100 / 1 to 10 / 1). 3 -methoxy-6-methyl-l -naphthyl trifluoromethanesulfonate (7.70 g, 24.0 mmol, 96.2 % yield, 99.9 % purity) was obtained as a colorless oil. ESI MS m / z 320.7[M+H]+.

[0314] The following intermediates were prepared according to the preparation for Intermediate 3, substituting the appropriate phenol for 2-bromo-3-fluorophenol.Intermediate 442-bromo-3 -fluoro- 1 -(methoxymethoxy)-4-methylbenzene

[0315] Step 1 : 3-fluoro-4-methylphenol (1.016 g, 8.055 mmol) was placed in Cs2(3.9 mL, 64.44 mmol) and was cooled to 0°C. Br2(0.4150 mL, 8.055 mmol) was added and the mixture was stirred at room temperature for 2 hrs. 10% Na2S202was added and the mixture was extracted with DCM. The organic layers were combined, dried and filtered to provide 2-bromo-3-fluoro- 4-methylphenol (1.389 g, 6.775 mmol, 84.10 % yield) which was used directly in the next step.

[0316] Step 2: 2-bromo-3-fluoro-l-(methoxymethoxy)-4-methylbenzene was prepared according to the procedure for Intermediate 8 using 2-bromo-3-fluoro-4-methylphenol in place of 2-bromo-3-fluorophenol.Intermediate 452-bromo- 1 -isopropoxy-4-(methoxymethoxy)benzene

[0317] Step 1 : 4-isopropoxyphenol (1.00 g, 6.57 mmol) and TEA (1.83 mL, 13.1 mmol) were placed in DCM (25 mL). Acetyl chloride (7.56 mL, 7.56 mmol) was added dropwise and the reaction was stirred at room temperature for 2hr. Water was added and the mixture was extracted with DCM. The organic layer was dried, fdtered and concentrated to provide 4- isopropoxyphenyl acetate (1.24 g, 6.38 mmol, 97.2 % yield) which was directly in the next step.

[0318] Step2: 4-Isopropoxyphenyl acetate (1.24 g, 6.585 mmol) was placed in ACN (20 mL) and N-bromosuccinimide (1.173 g, 6.590 mmol) was added. The mixture was stirred for 18 hr. Water was added and the mixture was extracted with ether. The organic layers were combined, dried, and concentrated to provide 3-bromo-4-isopropoxyphenyl acetate (1.584 g, 5.800 mmol, 88.00 % yield) which was directly in the next step.

[0319] Step 3: 3-Bromo-4-isopropoxyphenyl acetate (500 mg, 1.83 mmol) was placed in MeOH (7 mL). A solution of KOH (111 mg, 1.98 mmol) in water (2 mL) was added to mixture and was stirred for 1 hr at room temperature. The reaction mixture was adjusted to pH 3 by the addition of IN HC1. The mixture was extracted with DCM. The extracts were combined, dried, fdtered and concentrated to provide crude 3-bromo-4-isopropoxyphenol which was used directly the next reaction.

[0320] Step 4: 2-Bromo-l -isopropoxy-4-(methoxymethoxy)benzene was prepared according to the procedure for Intermediate 8 using 3-bromo-4-isopropoxyphenol in place of 2-bromo-3- fluorophenolIntermediate 46l-bromo-3-chloro-2-isopropyl-5-(methoxymethoxy)benzene

[0321] Step 1 : l-bromo-3-chloro-2-isopropyl-5-methoxybenzene (952 mg, 3.61 mmol) was placed in DCM (3 mL) and was cooled to 0°C. BBr3 (9030 pL, 9.03 mmol) was added and the reaction was stirred at 0°C for 2 hr. Water was added and the mixture was extracted with DCM. The extracts were combined and concentrated. The resulting residue was purified by silica gel (0-20% EtOAc in hexane) to provide 3-bromo-5-chloro-4-isopropylphenol (575 mg, 2.30 mmol, 63.8 % yield)

[0322] Step 2: l-bromo-3-chloro-2-isopropyl-5-(methoxymethoxy)benzene was prepared according to the procedure for Intermediate 8 using 3-bromo-5-chloro-4-isopropylphenol in place of 2-Intermediate 47l-iodo-3-(methoxymethoxy)naphthalene

[0323] To a solution of 4-iodonaphthalen-2-ol (0.80 g, 3.0 mmol) in DCM (20 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.1 mL, 5.9 mmol) and chloro(methoxy)methane (0.29 g, 3.6 mmol) and the reaction stirred at room temperature for 4 hours, with additionalchloro(methoxy)methane (0.15 g) being added after 2 hours. The reaction was washed with brine and concentrated in vacuo. The material was purified by chromatography using a gradient of 0 to 10% EtOAc / hexanes as the eluent to give l-iodo-3-(methoxymethoxy)naphthalene (0.80 g, 2.5 mmol, 86 % yield).Intermediate 483-benzyloxy- 1 -bromo-naphthalene

[0324] Step A: 2,4-dibromonaphthalen-l -amine: To a solution of Br2(246 g, 1.54 mol, 79.3 mL) in AcOH (750 mL) was added a solution of naphthalen-l -amine (101 g, 705 mmol, 99.0 mL) in AcOH (500 mL) at room temperature and the reaction stirred at 70 °C for 1 hour. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with AcOH (300 mL). The solid was next suspended in 20 % aqueous ofNaOLI (1.2 L). The mixture was stirred for 20 minutes and filtered. The solid was washed with water (1 L) and dried under vacuum to give 2,4-dibromonaphthalen-l -amine (200 g, 664 mmol, 94.2% yield) as gray solid. ES+APCI MS m / z 301.9 [M+H]+.

[0325] Step B: 4-bromo-l -diazonio-naphthalen-2-olate: To a solution of 2,4-dibromonaphthalen- 1 -amine (60.0 g, 199 mmol) in AcOH (900 mL) and propionic acid (150 mL) was added NaN02(16.5 g, 239 mmol, 13.0 mL) portionwise at 5-8 °C over 30 minutes and the reaction mixture stirred at 5-8 °C for 30 minutes. The reaction mixture was poured into ice-water (4000 mL), the slurry filtered and the solid washed with water (2 x 50 mL) to give 4-bromo-l -diazonio- naphthalen-2-olate (150 g, wet crude) which was used crude in the next step immediately.’H NMR (400 MHz, CDCfi) d 8.12 - 8.10 (d, 7=8.4 Hz, 1H), 7.62 - 7.58 (t, 7=7.6 Hz, 1H), 7.41 - 7.37 (t, 7=7.6 Hz, 1 H), 7.31 - 7.29 (d, 7=8.0 Hz, 1 H), 7.20 (s, 1H).

[0326] Step C: 4-bromonaphthalen-2-ol: To a solution of 4-bromo-l-diazonio-naphthalen-2- olate (100 g, 402 mmol) in EtOH (2.00 L) was added portion- wise NaBH4(30.4 g, 803 mmol) at 13-15 °C over 1 hour and the reaction stirred at 15-18 °C for 3 hours. The reaction was filtered and concentrated to dryness. The residue was dissolved in DCM (1000 mL) and washed with water (500 mL x 2). The organics were dried over Na2S04and concentrated to dryness. The residue was purified by chromtography eluting with petroleum ether / EtOAc (60 / 1 -> 10 / 1) and material re-purified by reversed phase HPLC to give 4-bromonaphthalen-2-ol (40.0 g, 139 mmol, 17.3 % yield, 77.4% purity) as a gray solid. 'PI NMR (400 MHz, CDCI3) d 8.07 - 8.05 (d, J=8.0 Hz, 1H), 7.60 - 7.58 (d, J=7.6 Hz, 1H), 7.41 - 7.36 (m, 3H), 7.07 (s, 1H).

[0327] Step D: 3-benzyloxy-l-bromo-naphthalene: A mixture of 4-bromonaphthalen-2-ol (30.0 g, 134 mmol), BnBr (25.3 g, 148 mmol, 17.6 mL) and K2CO3 (55.7 g, 403 mmol) in MeCN (500 mL) was heated at 80 °C for 1 hr. The reaction mixture was filtered and concentrated to dryness. The residue was purified by silica gel column eluting with PE / EA (100 / 1 to 60 / 1) to give 3-benzyloxy-l -bromo-naphthalene (40.0 g, 128 mmol, 95 % yield).]H NMR (400 MHz, CDCI3) 8 8.19 - 8.17 (d, ,7=8.0 Hz, 1H), 7.75 - 7.32 (d, J=8.8 Hz, 1H), 7.64 - 7.63 (d, J=2.4 Hz,IH), 7.52 - 7.37 (m, 7H), 7.23 - 7.21 (d, J=2.0 Hz,IH), 5.2 (s, 2H).Intermediate 49 benzyl 4-(7-(3-(benzyloxy)naphthalen-l-yl)-2-(methylsulfinyl)-5,6,7,8- tetrahydiOpyrido[3,4-d]pyrimidin-4-yl)piperazine-l-carboxylate

[0328] Step A: tert- butyl 4-hydroxy-2-methylsulfanyl-6.8-dihyd)O-5 / 7-pyrido[3.4-dipyrimidiiie- 7- carboxyl ate: To a solution of 1 -tert-butyl 4-ethyl 3-oxopiperidine-l ,4-dicarboxylate (50.0 g, 184 mmol) in MeOH (1.00 L) under nitrogen was added NaOMe (49.8 g, 921 mmol) and 2- methylisothiourea (62.4 g, 331 mmol, H2SO4). The reaction mixture was stirred at 25 °C for 16 hours. HC1 (2 M) was added to the reaction mixture until pH~5 and then the mixture was concentrated under reduced pressure. The residue was suspended in 300 mL of ethyl acetate and 300 mL of water. The suspension was filtered. The organic phase was washed with water (1 x 300 mL), brine (l x 200 mL), dried over Na2S04, filtered and concentrated to give / er / -butyl 4- hydroxy-2-methylsulfanyl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidine-7- carboxylate (51.0 g, 138 mmol, 75.4 % yield, 81.0 % purity) which was used directly in the next reaction. ES+APCI MS m / z 298.2 [M+H]+.

[0329] Step B: tert- butyl 2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-57 / - pyrido [ 3 ,4-d]pyrimidine-7-carboxylate: To a solution of / <? / 7-butyl 4-hydroxy-2-methylsulfanyl- 6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidine-7-carboxylate (51.0 g, 171 mmol) in DCM (500 mL) was added DIEA (44.3 g, 343 mmol, 59.9 mL) and Tf20 (72.6 g, 257 mmol, 42.4 mL) sequentially at 0 °C under nitrogen. The reaction mixture was warmed up to 25 °C and stirred for 16 hours. The reaction mixture was concentrated and the residue purified by columnchromatography eluting with EtOAc / Petroleum 0 -> 10% to give / er / -butyl 2-methylsulfanyl-4- (trifluoromethylsulfonyloxy)-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidine-7-carboxylate (46.0 g, 107 mmol, 62.4 % yield). ES+APCI MS m / z 430.2 [M+H]+.

[0330] Step C: fcr / -butyl 4-(4-benzyloxycarbonvIpiperazin-l-yl)-2-methylsulfanyl -6,8-dihydro- pyrido [ 3 ,4-d]pyrimidine-7 -carboxylate : To a solution of / e;7-butyl 2-methylsulfanyl-4- (trifluoromethylsulfonyloxy)-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidine-7-carboxylate (46.0 g, 107 mmolin DMF (500 mL) was added DIEA (27.7 g, 214 mmol, 37.4 mL) and benzyl piperazine- 1 -carboxylate (25.9 g, 117 mmol, 22.7 mL). The reaction was heated to 100 °C for one hour under N2atmosphere. The reaction mixture was poured into ethyl acetate (300 mL). The mixture was washed with H20 (300 mLc3). The organic phase was washed with brine (200 mL), dried over anhydrous Na2S04, concentrated in vacuo. The residue was purified by column chromatography using 0->20% EtOAc / Petroleum as eluent to give / e / 7-butyl 4-(4- benzyloxycarbonylpiperazin-l-yl)-2-methylsulfanyl -6,8-dihydiO-57 / -pyrido[3,4-d]pyrimidine- 7-carboxylate (51.0 g, 96.9 mmol, 90.5 % yield, 92.0 % purity) ES+APCI MS m / z 500.3[M+H]+.

[0331] Step D: Benzyl 4-(2-methylsulfanyl-5.,6,7,8-tetrahvdropyrido[3,4-d]pyrimidin-4- yl)piperazine-l -carboxylate: To a solution of tert- butyl 4-(4-benzyloxycarbonylpiperazin-l- yl)-2-methylsulfanyl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidine-7-carboxylate (25.0 g, 50 mmol) in DCM (50 mL) was added TFA (85.6 g, 750 mmol, 55.6 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and theresidue was dissolved in 300 mL of ethyl acetate and 300 mL of water and Na2C03added until pH~8. The organic layer was washed with water (1c300 mL ), brine(l x 200 mL) and dried over Na2S04, filtered and concentrated under reduced pressure to give benzyl 4-(2- methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-l -carboxylate. The product was used directly to the next step without further purification. ES+APCI MS m / z 400.2 [M+H]+.

[0332] Step E: benzyl 4-[7-(3-benzyloxy-l-naphthyl)-2-methylsulfanyl-6,8-dihvdro-pyridoi3,4-d| pyrimidin-4-yllpiperazine-l -carboxylate: A mixture of 3-benzyloxy-l -bromo- naphthalene (16.3 g, 52.1 mmol) , benzyl 4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazine-l -carboxylate (16.0 g, 40.1 mmol), Cs2C03(32.6 g, 100 mmol), Pd2(dba)3(5.50 g, 6.01 mmol) and RuPhos (3.74 g, 8.01 mmol) in dioxane (300 mL) was degassed with N23 times and the mixture stirred at 85 °C for 5 hour under N2atmosphere. The reaction mixture was quenched by addition water (200 mL) at 0 °C, and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 10- 20% MeOH / DCM to give benzyl 4-[7-(3-benzyloxy-l- naphthyl)-2-methylsulfanyl-6,8-dihydro-5 / / -pyrido[3,4-d] pyrimidin-4-yl]piperazine-l- carboxylate (16.0 g, 22.8 mmol, 56.9 % yield, 90.0 % purity ES+APCI MS m / z 632.5 [M I II]+.

[0333] Step F: benzyl 4-r7-(3-benzyloxy-l-naphthyl)-2-methylsulfinyl-6,8-dihydro-pyrido[3,4-d lpyrimidin-4-vHpipcrazine- l -carboxylate: To a solution of benzyl 4-[7-(3- benzyloxy-1 -naphthyl)-2-methylsulfany]-6,8-dihydro-5 / / -pyndo[3,4-d]pyrimidin-4- yl]piperazine-l-carboxylate (8.00 g, 12.7 mmol) in DCM (200 mL) was added m-CPBA (2.73 g, 12.7 mmol, 80.0 % purity) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for two hours under 0 °C. The reaction mixture was quenched by addition Na2S203(10 mL) at 0 °C, and then diluted with water (100 mL) and extracted with DCM (200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 0- l0% MeoH / DCM to benzyl 4-[7-(3-benzyloxy-l-naphthyl)-2-methylsulfinyl- 6,8-dihydro-5 / 7-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (3.50 g, 4.92 mmol, 38.8 % yield, 91.0 % purity) ES+APCI MS m / z 648.5 [M+H]+.Intermediate 50 / er / -butyl 4-(4-benzyloxycarbonylpiperazin-l -yl)-2-methylsulfonyl-6,8-dihydro- 5 H- pyrido [3 ,4-d]pyrimidine-7-carboxylateCbzCbz

[0334] Step A: tert- butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2-methylsulfonyl-6,8-dihydro- 5 / / -pyrido [ 3 ,4-d]pyrimidine-7 -carboxylate : To a stirred solution of / er / -butyl4-(4- benzyloxycarbonylpiperazin -l-yl)-2-methylsulfanyl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidine- 7-carboxylate (14.4 g, 28.9 mmol) in DCM (150 mL) was added m-CPBA solid (17.4 g, 101 mmol) at 0 °C under nitrogen. After stirring at 0 °C for 2 hours, the reaction mixture was diluted with water (300 mL) and basified with saturated NaHC03aqueous solution to pH ~ 8 and then extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (3x200 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate 10 / 1 to 1 / 2) to give tert- butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2-methylsulfonyl-6, 8-dihydro- 5 / / -pyrido[3,4- d]pyrimidine-7-carboxylate (1 1.0 g, 19.7 mmol, 68.6 % yield, 95.4 % purity). ES+APCI MS m / z 532.1 [M+H]+.Intermediate 514-bromo-5-methyl-l-tetrahydropyran-2-yl-indazole

[0335] Step A: 4-biOmo-5-methyl-l -tetrahvdlOpyran-2-yl-indazole: To a mixture of 4-bromo-5- methyl-177-indazole (3 g, 14.2 mmol) and 3,4-dihydro-277-pyran (2.39 g, 28.4 mmol, 2.60 mL) in DCM (30 mL) was added TsOH*H20 (270 mg, 1.42 mmol) and the mixture stirred at 15 °C for 2 hours. After completion, the reaction mixture was concentrated under vacuum and the residue purified by column chromatography using 5~>20& EtOAc / Petroleum Ether as eluent to give 4-bromo-5-methyl-l-tetrahydropyran-2-yl-indazole (4 g, 13.6 mmol, 95.3% yield) as white solid. Ή NMR (400 MHz, chloroform-d) d 8.01 (s, 1H), 7.47 (d, 7=8.4 Hz, 1H), 7.25 (d, 7=8.4 Hz, 1H), 5.70 (dd, 7=2.8, 9.2 Hz, 1H), 4.05 - 3.96 (m, 1H), 3.79 - 3.70 (m, 1H), 2.66 - 2.44 (m, 4H), 2.25 - 2.04 (m, 2H), 1.84 - 1.56 (m, 3H).Intermediate 524-bromo-5-methoxy- 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-indazole

[0336] 4-bromo-5-methoxy-l -(tetrahydro-2H-pyran-2-yl)-l H-indazole was prepared following Intermediate 51 substituting 4-bromo-5-methoxy-l H-indazole for 4-bromo-5-methyl-l / / - indazole in Step A. 'H NMR (400 MHz, chloroform-d) d 8.00 (s, 1H), 7.53 (d, 7=9.2 Hz, 1H), 7.16 (d, =9.2 Hz, 1 H), 5.70 (dd, 7=2.8, 9.2 Hz, 1 H), 4.04 - 3.98 (m, 1H), 3.96 (s, 3H), 2.55 - 2.49 (m, 1H), 2.23 - 2.05 (m, 2H), 1.83 - 1.69 (m, 3H).Intermediate 533-(benzyloxy)-l -bromo-2-methylnaphthalene

[0337] Step A: ethyl 2-methyl-3-oxo-4-phenyl-butanoate. To a dried 250 ml three-necked flask was added ethyl 3-oxo-4-phenyl-butanoate (4.00 g, 19.4 mmol.), THF (50.0 mL), sodium hydride (931 mg, 23.3 mmol) and the reaction stirred for 0.5 hours at 0°C. A solution of methyl iodide (3.03 g, 21.3) was next added drop-wise. After addition was completed, the reaction mixture was warmed to 20 °C and stirred for two hours at 20°C. The reaction mixture was quenched by addition of water (10.0 mL) at 20 °C and then diluted with ethyl acetate (20.0 mL) and the layers separated. The aqueous layer was next extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether : Ethyl acetate 20:1 to 10: 1) to give ethyl 2-methyl-3-oxo-4-phenyl-butanoate (3.60 g, 16.3 mmol, 84.3% yield) as a colorless oil. 'H NMR (400 MHz, CDC13) d = 7.38 - 7.28 (m, 3H), 7.25 - 7.19 (m, 2H), 4.22 - 4.15 (m, 2H), 3.87 (d, ,7= 2.0 Hz, 2H), 3.65 (q, J = 7.2 Hz, 1H), 1.34 (d, J = 7.2 Hz, 3H), 1.30 - 1.26 (m, 3H).

[0338] Step B: 2-methylnaphthalene-l ,3-diol. A solution of ethyl 2-methyl-3-oxo-4-phenyl- butanoate (3.60 g, 16.3 mmol) in concentrated sulfuric acid (19.9 g, 203 mmol) was stirred at 15 °C for 12 hours. The reaction mixture was poured into ice-water (30.0 mL) and the resulting solid collected by filtration and dried under vacuum to afford 2-methylnaphthalene-l,3-diol (1.80 g, 10.3 mmol, 63.2% yield) as a red solid. *H NMR (400 MHz, CDCb) d = 8.02 (d, . / =8.0 Hz, 1H), 7.65 - 7.54 (m, 1H), 7.41 (t, .7= 7.2 Hz, 1H), 7.36 - 7.31 (m, 1H), 6.80 (s, 1H), 4.29 - 4.20 (s, 2H), 2.41 - 2.24 (s, 3H).

[0339] Step C: 3 -methoxy-2-methyl-naphthalen- 1 -ol . 2-methylnaphthalene-l,3-diol (1.70 g, 9.76 mmol) was added to HCl / MeOH (2 M, 35.0 mL) and the result mixture was stirred at 30 °C for 3 days. The reaction was concentrated in vacuo and the residue purified by Prep-TLC(Petroleum ether : Ethyl acetate 1 :1) to give 3-methoxy-2-methyl-naphthalen-l-ol (800 mg, 4.25 mmol, 43.5% yield) as a white solid. Ή NMR (400 MHz, CDCl3) d = 8.02 (d, J= 8.4 Hz, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.37 - 7.31 (m, 1H), 6.79 (s, 1H), 5.14 (s, 1H),3.94 (s, 3H), 2.29 (s, 3H).

[0340] Step D: (3-methoxy-2-methyl- 1 -naphthyPtrifluoromethanesulfonate. To a mixture of 3- methoxy-2-methyl-naphthalen-l-ol (800 mg, 4.25 mmol.) and pyridine (504 mg, 6.38 mmol) in DCM (10.0 mL) was added trifluoroacetic anhydride (1.44 g, 5.10 mmol) dropwise at 0°C under N2atmosphere. The mixture was warmed to 20°C and stirred for an additional 5 hours. The solvent was removed under vacuum and the residue purified by Prep-TLC (Petroleum ether : Ethyl acetate 1 :1) to give (3-methoxy-2-methyl-l -naphthyl)trifluoromethanesulfonate (1.30 g, 4.06 mmol, 95.5% yield) as a white solid. Ή NMR (400 MHz, CDC13) d = 7.97 (d, J= 7.6 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.52 - 7.43 (m, 2H), 7.14 (s, 1H), 3.99 (s, 3H), 2.42 (s, 3H)

[0341] Step E: l-bromo-3-methoxy-2-methyl-naphthalene : In a sealed tube was added (3- methoxy-2-methyl-l-naphthyl)trifluoromethanesulfonate (466 mg, 1.45 mmol), t-Bu-Brettphos (154 mg, 290 umol), potassium bromide (259 mg, 2.17 mmol), PEG-200 (175 mg), 2-butanone (157 mg, 2.17 mmol) and Pd2(dba)3(133 mg, 145 umol) in toluene (10.0 mL) and the mixture de-gassed with N2 for 5 minutes. Next, triisobutylaluminum (431 mg, 2.17 mmol) was added drop-wise at 20 °C. The mixture was heated to 100 °C for 24 hrs. The reaction mixture was poured into water (30.0 mL) and the aqueous layer extracted with ethyl acetate (20.0 mL x 3). The combined organics were washed with brine (30.0 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was pre-purified by column chromatography (Petroleum ethenEthyl acetate 10: 1) and then by Prep-TLC (Petroleum ether : Ethyl acetate 10:1) to give l-bromo-3-methoxy-2 -methyl -naphthalene (700 mg, 2.79 mmol, 64.1% yield) as awhite solid. *H NMR (400 MHz, CDCb) d = 8.26 - 8.17 (m, 1H), 7.73 - 7.69 (m, 1H), 7.47 - 7.40 (m, 2H), 7.09 (s, 1H), 3.98 - 3.95 (m, 3H), 2.56 (s, 3H).

[0342] Step F: 4-bromo-3 -methyl-naphthalcn-2-ol : To a solution of l-bromo-3-methoxy-2- methyl-naphthalene (580 mg, 2.31 mmol) and tetrabutylammonium iodide (2.13 g, 5.78 mmol) in DCM (11.0 mL) cooled to -78 °C was added a solution of BCl3(1 M, 5.78 mL) dropwise over a period of 10 minutes while under N2. The reaction mixture was warmed to 0 °C and stirred for 2 hours at room temperature. Next the solvent was removed under vacuum and the residue was purified by Prep-TLC (Petroleum ether : Ethyl acetate 5: 1) to give 4-bromo-3- methyl-naphthalen-2-ol (500 mg, 2.1 1 mmol, 91.3% yield) as a white solid. 'H NMR (400 MFIz, CDCb) d = 8.26 - 8.15 (m, 1H), 7.63 (dd, J= 3.6, 6.0 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.11 (s, 1H), 5.09 (s, 1H), 2.60 (s, 3H), 1.56 (s, 3H).

[0343] Step G: 3-benzyloxy-l-bromo-2-methyl-naphthalene. To a mixture of 4-bromo-3- methyl-naphthalen-2-ol (265 mg, 1.12 mmol) and benzyl bromide (201 mg, 1.18 mmol) in acetonitrile (3.00 mL) was added potassium carbonate (310 mg, 2.24 mmol) in one portion at 20 °C under N2. The mixture was next stirred at 60°C for two hours. The solvent was removed under vacuum and the residue purified by Prep-TLC (Petroleum ether : Ethyl acetate 5:1) to give the 3-benzyloxy-l-bromo-2-methyl-naphthalene (250 mg, 695 umol, 31.0% yield, 91.0% purity) as a white solid. ES+APCI MS m / z 327.0, 329.0 [M+H]+.Intermediate 54 er / -butyl-2-(cyanomethyl)-4-[2-[[(2S)-l-methylpyriOlidin-2-yl]methoxy]-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate

[0344] Step A: (4-bromo-2-naphthyl) 2.2-dimethylpropanoate. To a solution of 4- bromonaphthalen-2-ol (10 g, 44.8 mmol) and TEA (9.07 g, 89.7 mmol) in DCM (200 mL) was added 2,2-dimethylpropanoyl chloride (8.11 g, 67.2 mmol) at 0°C. The reaction mixture was stirred at 0 °C for 10 min. T reaction mixture was quenched by addition of water (50 mL) and the layers separated. The organic layer was washed with brine (30 mL), dried over Na2S04filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (PE: EA =1 :0 to 100:1) to give (4-bromo-2-naphthyl) 2,2-dimethylpropanoate (9 g, 29.3 mmol, 65.4% yield) as a red oil. 1H NMR (400MHz, CHLOROFORM-d) d = 8.22 (d, 7=8.0 Hz, 1H), 7.83 - 7.77 (m, 1H), 7.63 - 7.49 (m, 4H), 1.41 (s, 9H).Intermediate 55 / er / -butyl 4-(2-(3-morpholinopiOpoxy)-5,6,7,8-tetrahydiOpyrido[3,4-d]pyrimidin-4-yl) piperazine- 1 -carboxylate.

[0345] Step A: 7-benzyl-6,8-dihvdro-5 / / -pyrido[3,4-f|pyrimidine-2,4-diol· To EtOH (600 mL) was added Na (5.56 g, 241 mmol) in portions and the mixture stirred for 1 hour. To this solution was added ethyl 1 -benzyl-3 -oxo-piperidine-4-carboxylate (30.0 g, 100 mmol) and urea (14.5 g, 242 mmol) and the reaction mixture stirred at 75 °C for 36 hours. The solvent was removed under vacuum and the residue dissolved in water (50 mL) and acidified by addition of HC1 (120 mL, 2M) at which point a solid precipitated. The solid was filtered and the filter cake dried under vacuum to give 7-benzyl-6,8-dihydro-577-pyrido[3,4-<f]pyrimidine-2,4-diol (22.0 g, 83.8 mmol). *HNMR (400MHz, DMSO-d6) d = 10.97 (br s, 1H), 10.66 (br s, 1H), 7.55 - 6.95 (m, 5H), 3.81 - 3.50 (m, 2H), 3.26 - 2.91 (m, 2H), 2.77 - 2.58 (in, 2H), 2.34 - 2.09 (m, 2H).

[0346] Step B: 7-benzyl-2.4-dichloro-6,8-dihvdro- pyrido[3.4-d]pyrimidine. To a solution ofDIEA (30.1 g, 233 mmol) in POCl3(330 g, 2.15 mol) was added 7 -benzyl-6, 8-dihydro-5 / 7- pyrido[3,4-d] pyrimidine-2, 4-diol (20.0 g, 77.7 mmol) and the reaction mixture stirred at 110 °C for 5 hours. Upon completion, the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (400 mL) and poured into sat. NaHC03(200 mL) and the layers separated. The aqueous layer was extracted with DCM (2 x 400 mL). The combined organics were washed with brine (100 mL), dried over Na2S04and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / DCM = 10 / 1 to 0 / 1) to give 7-benzyl- 2,4-dichloro-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidine (7.70 g, 26.2 mmol).1HNMR (300MHz, chloroform-d) 5 = 7.43 - 7.28 (m, 5H), 3.73 (s, 2H), 3.66 (br s, 2H), 2.84 (br s, 4H).

[0347] Step C: / e / - / -butyl 4-(7-benzyl-2-chloro-6,8-dihvdro-5 / / -pyrido[3,4-d]pyrimidin-4-yl) piperazine- 1 -carboxylate. To a solution of 7-benzyl-2,4-dichloro-6,8-dihydro-5 / 7- pyrido[3,4- tTjpyrimidine (17.3 g, 58.8 mmol) in DMSO (200 mL) was added DIEA (19.0 g, 147 mmol) and terl- butyl piperazine- 1 -carboxylate (11.5 g, 61.7 mmol) and the mixture stirred at 55 °C for 10 hours. The reaction mixture was poured into ethyl acetate (200 mL) and washed with water (3x200mL). The combined organics were washed with brine (200 mL), dried over anhydrous Na2S04and concentrated under vacuum to give a residue. The residue was purified by trituration from MTBE (200 mL) to give tert- butyl 4-(7-benzyl-2-chloro-6,8-dihydro-5 / / - pyrido[3,4-d]pyrimidin-4-yl) piperazine- 1 -carboxylate (24 g, 52.9 mmol). ES+APCI MS m / z 444.2 [M+H]+.

[0348] Step D: tert- Butyl 4-l 7-bcnzyl-2-i3-morpholinoproDoxy)-6.8-dihydro- pyrido[3.4-dlpyrimidin-4-nP piperazine- 1 -carboxylate. A mixture of 3-morpholinopropan-l-ol (1 1.8 g,81.1 mmol), tert- butyl 4-(7-benzyl-2-chloiO-6,8-dihydro-5 / / -pyrido[3,4-ri]pyrimidin-4- yl)piperazine-l- carboxylate (18 g, 40.5 mmol), BINAP (5.05 g, 8.11 mmol), / -BuONa (9.74 g, 101 mmol) and Pd2(dba)3(3.71 g, 4.05 mmol) in toluene (300 mL) was degassed and purged with N23 times, and the mixture stirred at 110 °C for 3 hours under N2atmosphere. The reaction mixture was poured into H20 (200 mL) and the aqueous layer extracted with ethyl acetate (3x300 mL). The combined organics were washed with brine (200 mL), dried over anhydrous Na2S04and concentrated under vacuum to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate = 100 / 1 to 5 / 1) to give tert- Butyl 4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-4-yl] piperazine- 1 -carboxylate (14 g, 22.5 mmol). ES+APCI MS m / z 553.4 [M+H]+.

[0349] Step E: fe / 7-butyl 4-[2-(3-morpholinopropoxy)-5.6,7,8-tetrahvdropyrido[3,4-< ]pyrimidin- 4-yll piperazine- 1 -carboxylate. To a solution of / er / -butyl 4-[7-benzyl-2-(3- morpholinopropoxy)- 6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-4-yl]piperazine-l -carboxylate (14 g, 25.3 mmol) in MeOH (1 L) was added dry Pd / C (3 g, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15 psi) at 40 °C for 10 hours. The mixture was filtered and the filtrate concentrated in vacuo to give a residue. The residue was purified by reversed phase flash [water (0.1TFA) / acetonitrile] to give tert- butyl 4-[2-(3-morpholinopropoxy)-5, 6,7,8- tetrahydropyrido[3,4-<7]pyrimidin-4-yl] piperazine- 1 -carboxylate (6.5 g, 13.9 mmol). ES+APCI MS m / z 463.4 [M+H]+.Intermediate 56

[0350] Naphthalen-l -yl trifluoromethanesulfonate. alpha-Naphthol (4 g, 27.74 mmol) was dissolved in DCM (200 mL) in a 3 neck flask. The reaction was cooled to 10°C in a water bath.N-ethyl-N-isopropylpropan-2-amine (4.846 ml, 27.74 mmol) and trifluoromethanesulfonic anhydride (4.668 ml, 27.74 mmol) were added to the solution dropwise. The reaction was stirred at 10°C for 2 hours. TLC (25% EtOAc, UV vis) showed reaction complete. The organics were with water (2X) and brine (2X). The organics were dried over MgS04 and concentrated in vacuo. The concentrate was purified using normal phase chromatography on the CombiFlash (0%-l2% EtOAc:Hexanes). All fractions containing clean product were combined and conentrated in vacuo to give naphthalen-l-yl trifluoromethanesulfonate (6.77 g, 24.51 mmol, 88.34 % yield).Intermediate 57Tert-butyl (S)-2-(hydroxymethyl)-4-methylpiperazine-l-carboxylate

[0351] To a solution of (S)-l-Boc-2-hydroxymethylpiperazine (1.0 g, 4.62 mmol) in DCE (92.47 ml, 4.624 mmol) was added formaldehyde (3.474 ml, 46.24 mmol) (37% in water) followed by sodium triacetoxyborohydride (4.9 g, 23.12 mmol). The mixture was stirred vigorously at room temperature for 2.5hours. The mixture was treated with saturated sodium bicarbonate (30 mL) stirred for 10 min then extracted with DCM (3 x 10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated. ES+APCI MS m / z 231.1 [M+EI]+.Intermediate 58Tert-butyl (R)-2-(hydroxymethyl)-4-methylpiperazine- 1 -carboxylate

[0352] Title compound was prepared as in Intermediate 57, substituting tert-butyl (R)-2- (hydroxymethyl)piperazine-l -carboxylate for (S)-l -Boc-2-hydroxymethylpiperazine. ES+APCI MS m / z 231.1 [M+H]+Intermediate 59l-bromo-3-chloro-2-fluoiO-5-(methoxymethoxy)benzene

[0353] To a round bottom flask was added THF (8.87 ml, 4.44 mmol) followed by sodium hydride, 60 % dispersion in mineral oil (0.213 g, 5.32 mmol). The mixture was cooled to 0 °C then 3-bromo-5-chloro-4-fluoiOphenol (1.0 g, 4.44 mmol) was added portionwise. Once the bubbling had ceased the resulting dark mixture was stirred at 0 °C for 30 min. Thenchloromethyl methyl ether (0.421 ml, 5.54 mmol) was added and the mixture was warmed to ambient temperature where it was stirred for 2 hr. A saturated aqueous ammonium chloride solution was added and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated. Crude material was chromatographed (0-15% EtOAc in hexanes) to provide product as clear oil.Intermediate 604-bromo-l -tetrahydropyran-2-yl-5-(trifluoromethyl)indazole

[0354] Step A: 4-bromo-l-tetrahvdropyran-2-yl-5-(trifluoromethyl)indazole: To a solution of 4- bromo-5-(trifluoromethyl)-lEI-indazole (500 mg, 1.89 mmol, 1 eq) in DCM (10 mL) was added 3,4-dihydro-2H-pyran (476 mg, 5.66 mmol, 517 uL, 3 eq) and TsOELLLO (35.9 mg, 188 umol, 0.1 eq). The mixture was stirred at 15 °C for 1 hour. The mixture was concentrated. The residue was purified by column chromatography (Si02, PE:EA=l 0: l to 1 : 1) to give 4-bromo-l- tetrahydropyran-2-yl-5-(trifluoromethyl)indazole (480 mg, 1.37 mmol, 72.9% yield) as yellow oil. 'Ll NMR (400 MHz, chloroform-d) 5 8.20 (s, 1H), 7.69 - 7.63 (m, 2H), 5.70 (dd, J= 2.8, 8.8 EIz, 1H), 4.05 - 3.96 (m, 1H), 3.79 - 3.70 (m, 1H), 2.56 - 2.50 (m, 1H), 2.27 - 2.04 (m, 2LI), 1.80 - 1.74 (m, 2H), 1.60 - 1.54 (m, 1H).Intermediate 61

[0355] 8-biOmo-6-(melhoxymethoxy)quinoline: A stirred suspension of 8-bromoquinolin-6-ol (1.00 g, 4.46 mmol) in DCM (20 mL) was cooled to 0°C and diisopropylethylamine (1.2 mL, 6.7 mmol, 1.5 eq.) was added followed by chloro(methoxy)methane (0.41 mL, 5.4 mmol, 1.2 eq.) dropwise and the reaction mixture was warmed to room temperature overnight.Concentrated aqueous ammonia (0.5 mL, ~5 mmol) was next added and the resulted mixture was stirred for lhour at room temperature. The mixture was evaporated in vacuo and chromatographed on silica gel, Redisep 40g, using 20% EtOAc / hexane as eluent to give a colorless powder (0.52 g, 44%). ES+APCI MS m / z 268.0, [M+H]4.Intermediate 62

[0356] To a solution of but-3-enenitrile (80.0 g, 1.19 mol, 96.4 mL, 1.00 eq) in / er / -butanol (130 mL) and petroleum ether (480 mL) was added a solution of Br2(191 g, 1.19 mol, 61.5 mL, 1.00 eq) in / cv7-butanol (130 mL). The mixture was stirred at 10 °C for 4 hours. The mixture was used into next step without any workup.

[0357] To the above mixture (274 mL) was added a solution of AyV’-dibenzyl ethane- 1 , 2-diamine (160 g, 445 mmol, 157 mL, 2 HOAc) and Et3N (178 g, 1 .76 mol, 245 mL) in toluene (300 mL). After was stirred at 1 10 °C for 2 hours, the mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was purified by column chromatography (Si02, petroleum ether / ethyl acetate = 3 / 1) to give 2-(l , 4-dibenzylpiperazin-2-yl)acetonitrile (75.0 g, 246 mmol, two steps 55.7 % yield) as a yellow solid. LCMS [ESI, M+l ]: 306.

[0358] ‘H NMR (400MHz, chloroform-d) d = 7.37 - 7.23 (m, 10H), 3.80 (d, = 13.2 Hz, 1H), 3.60 - 3.42 (m, 3H), 3.06 - 2.96 (m, 1H), 2.95 - 2.83 (m, 1 H), 2.69 - 2.53 (m, 4H), 2.52 - 2.35 (m, 3H).

[0359] To a solution of 2-(l ,4-dibenzylpiperazin-2-yl)acetonitrile (160 g, 524 mmol, 1.00 eq) in dichloroethane (1.50 L) was added 1 -chloroethyl carbonochloridate (300 g, 2.10 mol, 4.00 eq) at 15 °C. After stirred at 85 °C for 48 h, the mixture was concentrated under vacuum. The residue was then taken up into methanol (1.50 L) and heated to reflux for 1 hour. The mixture was concentrated. The solid was treated with methyl tert-butyl ether (1.00 L), 2-piperazin-2-ylacetonitrile (Intermediate 62, 90.0 g, 454 mmol, 86.7 % yield, 2HC1) was obtained as a white solid and used for next step without further purification.

[0360] Ή NMR (400MHz, DMSO-d6) d = 10.19 (br s, 2H), 4.01 - 3.73 (m, 1H), 3.69 - 3.41 (m, 4H), 3.32 (dt, J= 2.8, 13.2 Hz, 1H), 3.27 - 3.10 (m, 3H).Intermediate 63Cbz Cbz,Itwo steps yield: 72% Boc yield: 95% H

[0361] To a solution of / ert-butyl (3 / Z)-3-(hydroxymethyl)pipcrazine-l -carboxyl ate (80.0 g, 370 mmol, 1.0 e ) in Ethyl acetate (1400 mL) was added NaHC03(93.2 g, 1.1 1 mol, 43.2 mL, 3.0 eg), H20 (700 mL) and benzyl carbonochloridate (82.0 g, 481 mmol, 68.4 mL, 1.30 eg). The mixture was stirred at 25 °C for 12 hour. After completion, the organic phase was separated, washed with water (500 mL x 2) dried over Na2S04and filtered. The solvent was removed under vacuum to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate=40 / l to 1 / 1). The product l-benzyl 4- / ert-butyl (2R)-2- (hydroxymethyl)piperazine-l,4-dicarboxylate (85.0 g, 235 mmol, 64% yield, 96% purity) was obtained as a yellow oil. LCMS [ESI, M-99]: 251.

[0362] To a solution of l -benzyl 4- / ert-butyl (2R)-2-(hydroxymethyl)piperazine-l ,4- dicarboxylate (20.0 g, 57.1 mmol, 1.0 eq ) in 2-Methyltetrahydrofuran (240 mL) was added TEA (17.3 g, 171.23 mmol, 23.8 mL, 3.0 eq) and methanesulfonyl chloride (7.74 g, 67.6 mmol, 5.23 mL, 1.18 eq). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was quenched by addition H20 150 mL at 20 °C. The reaction mixture was extracted with Ethyl acetate (300 mL x 2). The organic layers were washed with H20 (100 mL), dried over Na2S04, and filtered. The solvent was removed under vacuum. 1 -benzyl 4- / ert-butyl (2R)-2-(methylsulfonyloxymethyl)piperazine-l,4-dicarboxylate (22.0 g, crude) was obtained as a yellow oil. The crude product was used directly to the next step without further purification.

[0363] To a solution of l-benzyl 4-tert-butyl (2f?)-2-(methylsulfonyloxymethyl)piperazine-l,4- dicarboxylate (22.0 g, 51.3 mmol) in DMA (150 mL) was added NaCN (10.4 g, 211 mmol).The mixture was stirred at 60 °C for 12 hour. The solvent was removed under vacuum to give a oil residue. The residue was diluted with H20 (40.0 mL) and extracted with Ethyl acetate (50.0 mL x 3). The combined organic layers were washed with saturated brine (80.0 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate=40 / l to 5:1) The product l-benzyl 4-tert-butyl (2S)-2-(cyanomethyl)piperazine-l,4-dicarboxylate (18.5 g, 46.4 mmol, two steps yield 72%) was obtained as a yellow oil. LCMS [ESI, M+l]: 360.

[0364] To a solution of l-benzyl 4-tert-butyl (26')-2-(cyanomethyl)piperazine-l ,4-dicarboxylatc (18.5 g, 43.3 mmol, 1.00 eq) in dioxane (40.0 mL) was added HCbdioxane (4 M, 54.1 mL, 5.0 eq). The mixture was stirred at 20 °C for 1 hour. Then the reaction mixture was added NaHC03to pH>7, and concentrated under reduced pressure to remove dioxane. The residue was diluted with H20 (50.0 mL) and extracted with Ethyl acetate (50.0 mL x 3). The combined organic layers were washed with H20 (20.0 mL) , dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The product benzyl (25 -2-(cyanomethyl)piperazine-l- carboxylate (Intermediate 63, 11.5 g, 91.8% purity, 95% yield) was obtained as a yellow oil. LCMS [ESI, M+l]: 260.

[0365] Ή NMR (400MHz, CHLOROFORM-d) d = 7.37 - 7.31 (m, 5H), 5.14 (s, 2H), 4.49 (br, s, 1H), 3.93 (br, s, 1H), 3.07 - 2.81 (m, 5H), 2.78 - 2.54 (m, 2H).Intermediate 64

[0366] A mixture of tert- butyl 2-methylsulfanyl-4 -(trifluoromethylsulfonyloxy)-6,8-dihydro- 57 / -pyrido[3,4-d]pyrimidine-7-carboxylate (3.81 g, 8.87 mmol, 1.0 eq), benzyl(2S)-2- (cyanomethyl)piperazine-l-carboxylate (Intermediate 63, 2.30 g, 8.87 mmol, 1.0 eq), DIEA (3.44 g, 26.6 mmol, 4.63 mL, 3.0 eq) in DMF (20.0 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 1 hour under N2atmosphere. After completion, the solvent was removed under vacuum. The residue was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate=3 / l to 1 :1) to give tert-bu y\ 4-[(3<S)-4- benzyloxycarbonyl-3-(cyanomethyl)piperazin-l-yl]-2-methylsulfanyl-6,8-dihydro-5 / / - pyrido[3,4-d]pyrimidine-7-carboxylate (3.6 g, 6.16 mmol, 69% yield, 92.2% purity) as a yellow solid. LCMS [ESI, M+l]: 539.

[0367] A mixture of / cr / -butyl 4-[(3S)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-l-yl]-2- methylsulfanyl-6,8-dihydro-5 / / pyrido[3,4-d]pyrimidine-7-carboxylate (6.0 g, 1 1.1 mmol, 1.0 eq), TFA (30.8 g, 270 mmol, 20.0 mL, 24.3 eq) in DCM (20.0 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 20 °C for 1 hour under N2atmosphere. After completion, the reaction mixture was quenched with saturated NaFICCb solution (500 mL). The mixture was extracted with ethyl acetate (3c300 mL) and the organic layer was dried over Na2S04and filtered. The solvent was removed under vacuum to give benzyl (2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-l- carboxylate (4.8 g, crude) as a yellow solid which was used for the next step without further purification.

[0368] A mixture of benzyl (25')-2-(cyanomethyl)-4-(2-methylsulfanyl-5, 6,7,8- tetrahydiOpyrido[3,4-d]pyrimidin-4-yl)piperazine-l-carboxylate (4.8 g), 1 -bromonaphthalene (3.8 g, 18.35 mmol, 2.55 mL), Pd2(dba)3(1.0 g, 1.09 mmol), RuPhos (1.02 g, 2.19 mmol) and Cs2C03(12.0 g, 36.8 mmol) in toluene (30.0 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 12 hours under N2atmosphere. After completion, the reaction mixture was filtered. The organic solvent was removed under vacuum to give an oil residue. The residue was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate=5 / l to 3:1) to give benzyl (2.V)-2-(cyanomethyl)-4-[2-methylsulfanyl-7-(l-naphthyl)- 6, 8-dihydro-577-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l -carboxylate (2.2 g, 3.31 mmol,85.3% purity, two steps yield 30%) was obtained as a yellow solid. LCMS [ESI, M+l]: 565.

[0369] A mixture of benzyl (25)-2-(cyanomethyl)-4-[2-methylsulfanyl-7-(l-naphthyl)-6,8- dihydro-57 / -pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (2.8 g, 3.97 mmol, 1.0 eq), m-CPBA (1.05 g, 5.16 mmol, 1.3 eq) in DCM (4.0 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 0 °C for 1 hour under N2atmosphere. After completion, the reaction is quenched by adding saturated Na2S03solution (50 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was dried with Na2S04and filtered. The solvent was removed to give a oil residue. The residue was purified by column chromatography (Si02, Metheanol / Ethyl acetate=l / 20 to 1 :10) to give benzyl ( 2S)-2 - (cyanomethyl)-4-[2-methylsulfinyl- 7-(l-naphthyl)-6,8-dihydro-57 / -pyrido[3,4-d]pyrimidin-4- yl]piperazine-l -carboxylate (Intermediate 64, 1.5 g, 2.35 mmol, 59% yield, 90.8% purity) as a yellow solid. LCMS [ESI, M+l ]: 581.Intermediate 65

[0370] To a solution of / er / -butyl 4-[(3A)-4-benzyloxycarbonyl -3-(cyanomethyl)piperazin-l-yl]- 2-methylsulfanyl-6,8-dihydro-5 / / -pyrido[3,4-<7]pyrimidine-7-carboxylate (24.3 g, 45.0 mmol,1.0 eq) in Ethyl acetate (480 mL) was added m-CPBA (8.69 g, 42.8 mmol, 85% purity, 0.95 eq) portionwise at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Upon completion, the mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (2 x 300 mL). The organic layers were dried over Na2S04and concentrated under vacuum. The residue was purified by reversed-phase flash [water (0.1% FA) / acetonitrile]. The mixture was neutralized with saturated sodium bicarbonate solution, concentrated under vacuum to remove MeCN and extracted with ethyl acetate (3 x 1000 mL). The organic layers were dried over Na2S04and concentrated under vacuum to give / er / -butyl 4-[(35)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-l-yl]-2- methylsulfinyl-6,8-dihydiO-57 / -pyrido[3,4- i]pyrimidine-7-carboxylate (22.8 g, 39.3 mmol, 87% yield, 95.8% purity) as a yellow solid.

[0371] Ή NMR (400 MHz, chloroform-d) d 7.37 - 7.23 (m, 5H), 5.12 (s, 2H), 4.75 - 4.41 (m,3 LI), 4.17 - 4.05 (m, 2H), 3.86 (d, J= 1 1.6 Hz, 1H), 3.81 - 3.62 (m, 1H), 3.46 - 3.18 (m, 3H), 3.10 (d, J- 3.6, 12.0 Hz, 1H), 2.81 (d, . / = 3.2 Hz, 3H), 2.77 - 2.56 (m, 4H), 1.42 (s, 9H).

[0372] To a solution of / er / -butyl 4-[(3£)-4-benzyloxycarbonyl- 3-(cyanomethyl)piperazin-l-yl]- 2-methylsulfinyl-6,8-dihydro-5 / / -pyrido[3,4-<i]pyrimidine-7-carboxylate (5.0 g, 9.01 mmol, 1.0eq ) and [(2S)- 1 -methylpyrrolidin -2-yl]methanol (1.82 g, 15.8 mmol, 1.88 mL, 1.75 eq) in toluene (50.0 mL) was added t-BuONa (1.73 g, 18.0 mmol, 2.0 eq). The mixture was stirred at 0 °C for 0.5 hour. After completion, the mixture was added cold water (50.0 mL) and extracted with ethyl acetate (5 x 50.0 mL). The combined organic layer was dried over Na2S04, filtered and concentrated. The obtained product was purified by column chromatography (Si02, PE :EA = 10:1 - EA : MeOH = 5:1) to give / er / -butyl 4-[(35)-4-benzyloxycarbonyl-3- (cyanomethyl)piperazin-l-yl]-2-[[(25)-l-methylpyriOlidin-2-yl]methoxy]-6,8-dihydro-577- pyrido[3,4- / ]pyrimidine-7-carboxylate (2.80 g, 4.62 mmol, 51.0% yield) as yellow solid.

[0373] 1H NMR (400 MHz, chloroform-d) d 7.44 - 7.35 (m, 5H), 5.21 (s, 2H), 4.73 - 4.54 (m, 2H), 4.44 - 4.33 (m, 2H), 4.22 - 4.10 (m, 2H), 3.41 - 3.93 (m, 1H), 3.82 (br d, J= 1 1.6 Hz, 2H), 3.39 - 3.22 (m, 3H), 3.11 (br t, J= 7.8 Hz, 1H), 2.99 (d, 7= 3.6, 12.8 Hz, 1H), 2.90 - 2.56 (m, 5H), 2.49 (s, 3H), 2.35 - 2.25 (m, 1H), 2.07 - 2.02 (m, 1H), 1.91 - 1.76 (m, 3H), 1.50 (s, 9H).

[0374] To a solution of tert-bxx\y\ 4-[(35)-4-benzyloxycarbonyl -3-(cyanomethyl)piperazin-l-yl]- 2-[[(25)-l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydiO-5 / / -pyrido[3,4-<7]pyrimidine-7- carboxylate (2.40 g, 3.96 mmol, 1.0 eq) in DCM (8.0 mL) was added TFA (13.9 g, 122 mmol, 9.0 mL, 30.7 eq). The mixture was stirred at 15 °C for 2 hours. After completion, the mixture was concentrated. The residue was added saturated Nal ICO3 aqueous (20.0 mL) and extracted with DCM (5 x 10.0 mL). The organic layer was dried over Na2S04, filtered and concentrated. The product benzyl (25)-2-(cyanomethyl)-4-[2-[[(25)-l-methylpyrrolidin-2-yl] methoxy]- 5,6,7,8-tetrahydropyrido[3,4-i7]pyrimidin-4-yl]piperazine-l -carboxylate (Intermediate 65, 1.40 g, 2.77 mmol, 70% yield) was obtained as yellow solid. LCMS [ESI, M+l]: 506.Intermediate 66,

[0375] Step A: To a solution of 7-benzyl-4-chloro-2-methylsulfanyl-6, 8-dihydro- 5 / 7- pyrido[3,4-d]pyrimidine (20.0 g, 65.4 mmol, 1 eq) in DCE (200 mL) was added 1 -chloroethyl carbonochloridate (28.1 g, 196 mmol, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and 70 °C for 15 hours. The mixture was concentrated under vacuum. The residue was dissolved in MeOH (200 mL) and stirred at 70 °C for 0.5 hours. Upon completion, the mixture was concentrated under vacuum. The residue was triturated with methyl / er / -butyl ether (60 mL). The precipitate was collected by filtration, washed with methyl / er / -butyl ether (20 mL) and dried under vacuum to give 4-chloro-2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4- djpyrimidine (17.2 g, crude, HC1) as a yellow solid which was used directly in the next step without further purification.

[0376] Ή NMR (400 MHz, methanol-d4) d = 4.35 (s, 2H), 3.60 (t, J= 6.4 Hz, 2H), 3.05 (t, J 6.4 Hz, 2H), 2.55 (s, 3H).

[0377] Step B: To a solution of 4-chloro-2-methylsulfanyl-5,6,7,8-tetrahydropyrido [3,4- djpyrimidine (16.5 g, crude, HC1) and TEA (20.0 g, 196 mmol, 27.3 mL) in THE (400 mL) was added benzyl carbonochloridate (16.7 g, 98.1 mmol, 13.9 mL) dropwise at 0 °C. The mixture was stirred at 25 °C for 0.5 hour. Upon completion, the mixture was diluted with water (80 mL) and the organic layer was separated. The aqueous phase was extracted with EtOAc (200 mL). The combined organic layers were dried over MgSOq, filtered and concentrated under vacuum.The residue was purified by silica gel chromatography (PE / EtOAc 80 / 1 to 5 / 1) to give benzyl 4- chloro-2-methylsulfanyl-6,8-dihydro-577-pyrido [3,4-d]pyrimidine-7-carboxylate (19.6 g, 50.4 mmol, two steps 86% yield, 90% purity) as a yellow oil.

[0378] JH NMR (300 MHz, chloroform-d) 5 = 7.37 (s, 5H), 5.18 (s, 2H), 4.63 (s, 2H), 3.877 (d, J= 8.0, 2H), 2.80 (br s, 2H), 2.54 (s, 3H).

[0379] Step C: To a solution of benzyl 4-chloro-2-methylsulfanyl-6,8-dihydro-5T / - pyrido[3,4- d]pyrimidine-7-carboxylate (21.5 g, 55.3 mmol, 1.00 eq ) in DMF (400 mL) was added DIEA (35.7 g, 277 mmol, 48.2 mL, 5.00 eq) and 2-[(2S -piperazin-2-yl]acetonitrile (6.92 g, 55.3 mmol, 1.00 eq). After stirred at 80 °C for 2 hours, (Boc)20 (60.4 g, 277 mmol, 63.5 mL, 5.00 eq) was added into above mixture and stirred at 80 °C for another 2 hours. Upon completion, the mixture was diluted with water (800 mL) and extracted with EtOAc (2 x 400 mL). The organic layers were washed with brine (300 mL), dried over Na2S04and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc 10 / 1 to 1 / 1) to give benzyl 4-[(3S)-4- / <?rf-butoxycarbonyl-3-(cyanomethyl) piperazin-l-yl]-2-methylsulfanyl-6,8- dihydiO-5 / / -pyrido[3,4-d]pyrimidine-7-carboxylate (24.3 g, 43.0 mmol, 78% yield, 95% purity) as a yellow solid.

[0380] *H NMR (400 MHz, chloroform-d) d - 7.43 - 7.29 (m, 5H), 5.18 (s, 2H), 4.76 - 4.54 (m, 2H), 4.46 (br d, J= 18.4 Hz, 1H), 4.08 - 3.69 (m, 4H), 3.53 - 3.35 (m, 1H), 3.34 - 3.03 (m, 2H), 3.03 - 2.89 (m, 1H), 2.81 - 2.55 (m, 4H), 2.50 (s, 3H), 1.51 (s, 9H).

[0381] Step D: To a solution of benzyl 4-[(3S)-4- / er / -butoxycarbonyl-3-(cyanomethyl) piperazin-l -yl]-2-methylsulfanyl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidine-7-carboxylate (24.3 g, 45.1 mmol, 1 eq) in EtOAc (480 mL) was added m- CPBA (8.70 g, 42.9 mmol, 85% purity, 0.95 eq) potionwise at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Upon completion, themixture was diluted with water (800 mL). The pH was adjusted to 8 with NaHC03and the organic layer was separated. The aqueous phase was extracted with EtOAc (2 x 400 mL). The organic layers were dried over Na2S04and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc / MeOH 100 / 1 to 10 / 1) to give benzyl 4-[(35 -4- tert-butoxycarbonyl-3-(cyanomethyl)piperazin-l-yl]-2-methylsulfinyl- 6,8-dihydro-5 / / - pyrido[3,4-<7]pyrimidine-7-carboxylate (20.9 g, 36.4 mmol, 81% yield, 96% purity) as a white solid. LCMS [ESI, M+l]: 555.

[0382] Step E: To a solution of benzyl 4-[(35)-4- / er / -butoxycarbonyl-3-(cyanomethyl) piperazin- l-yl]-2-methylsulfinyl-6,8-dihydro-5 / / -pyrido[3,4-i / ]pyrimidine-7-carboxylate (20.9 g, 37.6 mmol, 1 eg) and [(25)-l-methylpyrrolidin-2-yl]methanol (8.67 g, 75.3 mmol, 8.94 mL, 2 eq) in toluene (400 mL) was added / -BuONa (7.23 g, 75.3 mmol, 2 eq) at 0 °C. After stirred at 0 °C for 10 minutes, the mixture was concentrated under vacuum. The residue was diluted with water (200 mL) and extracted with EtOAc (2c400 mL). The organic layers were dried over Na2S04and concentrated under vacuum. The residue was purified by reversed-phase flash [water (0.1% FA) / acetonitrile] The mixture was neutralized with saturated sodium bicarbonate solution, concentrated under vacuum to remove MeCN and extracted with EtOAc (2 x 1000 mL). The organic layers were dried over Na2S04and concentrated under vacuum to give benzyl 4-[(3S)-4- / er / -butoxycarbonyl-3-(cyanomethyl)piperazin-l-yl]-2-[[(2*S)-l-methylpyrrolidin-2- yl]methoxy]-6,8-dihydro-5IT-pyrido[3,4-if]pyrimidine-7-carboxylate (13.5 g, 20.5 mmol, 54% yield, 92% purity) as a yellow solid. LCMS [ESI, M+l]: 606.

[0383] Step F: To a solution of benzyl 4-[(35)-4- / er / -butoxycarbonyl-3-(cyanomethyl) piperazin- l-yl]-2-[[(25 -l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-57 / -pyrido[3,4- ]pyrimidine-7- carboxylate (3.50 g, 5.78 mmol, 1 eq) in MeOH (60.0 mL) was added NFL / MeOH (60.0 mL), Pd / C (1.00 g, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15 psi) at 25 °C for 4 hours. Upon completion, the catalyst was filtered off and the filtrate was concentrated under vacuum to give tert- butyl (2S)-2-(cyanomethyl)-4-[2-[[(25)-l-methylpyrrolidin-2-yl] methoxy]-5, 6,7,8- tetrahydiOpyrido[3,4-d]pyrimidin-4-yl]piperazine-l -carboxylate (Intermediate 66, 2.33 g, 4.55 mmol, 79% yield, 92% purity) as a yellow solid which was used directly in the next step without further purification.

[0384] Ή NMR (400 MHz, chloroform-d) d = 4.58 (br s, 1H), 4.34 (dd, J= 5.2, 10.8 Hz, 1H),4.1 1 (dd, J = 6.8, 10.8 Hz, 1 H), 4.08 - 3.88 (m, 4H), 3.84 (br d, J= 12.8 Hz, 1H), 3.25 - 3.03 (m, 4H), 3.01 - 2.88 (m, 2H), 2.82 - 2.51 (m, 5H), 2.47 (s, 3H), 2.27 (dt, J= 7.2, 9.2 Hz, 1H),2.1 1 - 1.97 (m, 1H), 1.92 - 1.75 (m, 3H), 1.50 (s, 9H).Intermediate 67tert- butyl 2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5 / / -pyrido[3,4- d]pyrimidine-7-carboxylate

[0385] Step A: fe / 7-butyl 4-hydroxy-2-methylsulfanyl-6.8-dihydiO-5 / L / -pyrido[ 3,4-d Ipyrimidine- 7- carboxylate. To a stirred solution of 1 - / e / 7-butyl 4-ethyl 3-oxopiperidine-l ,4-dicarboxylate (50.0 g, 184 mmol, 1.00 eq ) in MeOH (1.00 L) at 25 °C under nitrogen was added NaOMe (49.8 g, 921 mmol, 5.00 eq), followed by 2-methylisothiourea (62.4 g, 331 mmol, 1.80 eq, H2S04) as a solid. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was acidified with HC1 (2 M) until pH~5, and then the mixture was concentrated under reduced pressure to removed MeOH. The residue was suspended in 300 mL of ethyl acetate and 300 mL of water and stirred rapidly. The suspension was filtered and the white solid was collected. The filtrate was separated and the organics washed with water (1 x 300 mL) and brine (l x 200 mL). The organics were isolated, dried over Na2S04, filtered and concentrated to a white solid tert- butyl 4-hydiOxy-2-methylsulfanyl-6,8-dihydro-5T / -pyrido[3,4-d]pyrimidine-7- carboxylate (51.0 g, 138 mmol, 75.4 % yield, 81 % purity) was obtained as a white solid and used directly for next step without further purification. LCMS [M+l] : 298.

[0386] *H NMR (400MHz, chloroform-d) d = 4.33 (s, 2H), 3.61 ( t, .7=5.6 Hz, 2H), 2.68 - 2.49 (m, 5H), 1.50 (s, 9H).

[0387] Step B: / er / -butyl 2-mcthyl sulfanyl-4-(tn(Tuoromethylsulionyloxy) -6,8-dihydro-5 / / - pyrido[3,4-dlpyrimidine-7-carboxylate. To a stirred suspension of / er / -butyl 4-hydroxy-2- methylsulfanyl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidine-7-carboxylate (51.0 g, 171 mmol, 1.00 eq) in DCM (500 mL) at 0 °C was added DIEA (44.3 g, 343 mmol, 59.9 mL, 2.00 eq), followed by Tf20 (72.6 g, 257 mmol, 42.4 mL, 1.50 eq) under nitrogen. Immediately a brown solution formed. After stirring at 25 °C for 16 hours, the reaction was concentrated to give a brown oil. The brown oil was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate = 1 / 0 to 10 / 1). Title compound / er / -butyl 2-methylsulfanyl-4-(trifluoromethylsulfonyloxy) -6,8- dihydro-5 / / -pyrido[3,4-d]pyrimidine-7-carboxylate (46.0 g, 107 mmol, 62 % yield) was obtained as a yellow solid. LCMS [M+l]: 430.Intermediate 68Cbz / er / -butyl 4-[(35)-4-benzyloxycarbonyl-3-(cyanomethyl)piperazin-l-yl]-2-methylsulfanyl-6,8- dihydro-5 / / -pyrido[3,4-d]pyrimidine-7-carboxylate

[0388] Step A: tert- butyl 4-[ -benzyloxycarbonyl-3 -( cyanomethyDpiperazin- 1 -yl] -2-methylsulfanyl-6.8-dihvdro- pyrido[3.4-d1pyrimidine-7-carboxylate· A mixture of / er / -butyl2-methylsulfanyl-4 -(trifluoromethylsulfonyloxy)-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidine-7- carboxylate(3.8l g, 8.87 mmol, 1.0 eq), benzyl(2S -2-(cyanomethyl)piperazine-l-carboxylate (Intermediate 63, 2.30 g, 8.87 mmol, 1.0 eq), DIEA (3.44 g, 26.6 mmol, 4.63 mL, 3.0 eq) in DMF (20.0 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 1 hour under N2atmosphere. After completion, the solvent was removed under vacuum. The residue was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate^ / l to 1 :1) to give title compound tert- butyl 4-[(3S -4-benzyloxycarbonyl-3- (cyanomethyl)piperazin- 1 -yl] -2-methylsulfanyl-6, 8-dihydro-57 / -pyrido [3 ,4-d]pyrimidine-7- carboxylate (3.6 g, 6.16 mmol, 69% yield, 92.2% purity) as a yellow solid.1985UB5TITUTE SHEET (RULE 26)Intermediate 691 -bromo-8-methylnaphthalene

[0389] Step A: 1 -bromo-8-methyl-naphthalene. To a solution of l ,8-dibromonaphthalene (1 g, 3.50 mmol, 1 eq) in THF (20 mL) was added MeLi (1.6 M in diethyl ether, 2.62 mL, 1.2 eq ) at 0°C dropwise. After stirring for 30 minutes at 0°C, iodomethane (3.38 g, 23.8 mmol, 1.48 mL, 6.81 eq) was added dropwise. The mixture was warmed up to 25°C and stirred for another 3 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18 250*50mm* l 0 um; mobile phase: [water (0.05% ammonia hydroxide v / v) - ACN]; B%: 45% - 70%, 28 MIN; 40% min). Ttitle compound l-bromo-8-methyl-naphthalene (340 mg, 1.49 mmol, 43% yield, 97% purity) was obtained as a yellow solid after lyophilisation.

[0390] Ή NMR (400MHz, chloroform-d) d = 7.75 (dd, J = 0.8, 7.2 Hz, 1H), 7.69 (dd, J= 0.8, 8.0 Hz, 1H), 7.66 - 7.59 (m, 1H), 7.30 - 7.22 (m, 2H), 7.13 (t, J= 8.0 Hz, 1H), 3.05 (s, 3H).Intermediate 7079%1 -bromo-8-chloronaphthalene

[0391] Step A: naphthoiL8-de1[L2,31triazine. To a solution of naphthalene- 1 ,8-diamine (100 g, 632 mmol, 1 eq) in AcOH (200 mL) and EtOH (1000 mL) was added isoamyl nitrite (72.6 g, 619 mmol, 83.4 mL, 0.98 eq) dropwise over a period of 2 h with temperature controlledbetween 18 and 21 °C under a cold-water bath. After the addition, the resulting red suspension was stirred at 25 °C for 16 hours. The solid was collected by filtration, washed with ethanol (2 x 500 mL) and dried under vacuum. Compound 1 / / -naphtho| 1 ,8-de j [1 ,2,3]triazine (84 g, 496 mmol, 79% yield) was obtained as a red crystalline solid and directly used next step without purification. LCMS [ESI, M+l]: 170.

[0392] Step B: 8-chloronaphthalen-l -amine. To a solution of l7 / -naphtho[l,8-de][l,2,3]triazine (84 g, 496 mmol, 1 eq ) in HC1 (1.5 L) was added Cu (2.10 g, 33.1 mmol, 234 uL, 0.0665 eq). The mixture was stirred at 25 °C for 12 hours. The resulting mixture was diluted with water (500 mL) and heated at 85 °C for 30 mins. The resulting almost clear aqueous solution was filtered, cooled, basified with aqueous ammonia (until blue to litmus paper) and the solution was extracted with ether acetate (2 x 1000 mL). The combined extracts were dried over Na2S04filtered and concentrated under vacuum. The residue was purified by column chromatography (Si02, Petroleum ether / Ethyl acetate = 200 / 1 to 5 / 1). Compound 8-chloronaphthalen-l -amine (57 g, 259 mmol, 52% yield, 81% purity) was obtained as a red solid. LCMS [ESI, M+l]: 178.

[0393] Step C: 1 -bromo-8-chloro-naphthalene. To a solution of 8-chloronaphthalen-l -amine (57 g, 320 mmol, 1 eq) and TsOH«H20 (219 g, 1.16 mol, 3.6 eq) in MeCN (1000 mL) was added a solution ofNaNCh (39.8 g, 577 mmol, 1.8 eq) and CuBr (138 g, 963 mmol, 29.3 mL, 3 eq) in H20 (120 mL) at - 5 °C, then the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was added saturated Na2S03solution (100 mL) and stirred for 15 mins, then extracted with ethyl acetate (1000 mLx3). The combined organic layers were washed with brine (500 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether). Title compound l-bromo-8-chloro-naphthalene (56 g, 229 mmol, 72% yield, 99% purity) was obtained as white solid.

[0394] Ή NMR (400MHz, chloroform-d) d = 7.93 (dd, J= 1.2, 7.6 Hz, 1H), 7.82 (dd, . / = 1.2, 8.4, 1H), 7.79 (dd, J= 1.2, 8.4, 1H), 7.67 (dd, . / = 1.2, 7.6 Hz, 1H), 7.37 (t , J= 8.0 Hz, 1H), 7.28 (t, J- 8.0 Hz, 1H).Intermediate 712-[(2S -4-[7-(8-chloro-l-naphthyl)-2-[[(2<?)-l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5 / 7- pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

[0395] Step A: 2-[(2M-4-[7-(8-chloro-l-naphthyr)-2-[[(2STl-methyl pyrrolidin-2-yllmethoxy]- 6,8-dihvdro-5 / / -pyridoi3.4- 4-yl]piperazin-2-yl |acetonitrile. To a solution of tert-butyl (25)-4-[7-(8-chloro-l-naphthyl)-2-[[(25)- l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro- 5 / / -pyrido[3,4-d]pyrimidin-4-yl]-2-(cyanomethyl)piperazine-l-carboxylate (0.5 g, 791 umol, 1 eq) in dioxane (5 mL) was added HCbdioxane (4 M, 5.00 mL, 25.3 eq ) at 0 °C. The mixture was stirred at 25 °C for 1 hour. Upon completion, the mixture was concentrated under vacuum to give an impure product (500 mg, crude, HC1) as a brown solid. 60 mg of the impure product was purified by prep-HPLC (column: Phenomenex Gemini l50*25mm* 10um; mobile phase: [water(0.04% NH3*H20 + lOmM NH4HCO3) - ACN]; B%: 50% - 80%, 10 min). The desired fractions were collected and lyophilized to give title compound 2-[(25)-4-[7-(8-chloro-l- naphthyl)-2-[[(25)-l -methyl pynOlidin-2-yl]methoxy]-6,8-dihydro-57 / -pyrido[3,4-d]pyrimidin- 4-yl]piperazin-2-yl]acetonitrile (19.3 mg, 36.1 umol, 34% purification yield, 99.2% purity) as a off-white solid. LCMS [ESI, M+l]:532.

[0396] Ή NMR (400 MHz, chloroform-d) d = 7.75 (d, J= 8.4 Hz, 1H), 7.60 (dd, . / = 1.6, 8.0 Hz, 1H), 7.52 (dd, ,7 = 0.8, 7.2 Hz, 1H), 7.44 (dt, J= 3.6, 7.6 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.22 (t, J = 6.8 Hz, 1H), 4.46 - 4.34 (m, 2H), 4.15 (td, .7=6.4, 10.6 Hz, 1H), 4.04 (br d, ,7=12.4 Hz, 0.5H), 3.95 - 3.79 (m, 2H), 3.74 (br d, .7=12.8 Hz, 0.5H), 3.63 - 3.48 (m, 1H), 3.40 - 2.99 (m, 7H), 2.98 - 2.80 (m, 2H), 2.73 - 2.61 (m, 1H), 2.60 - 2.49 (m, 3PI), 2.47 (d, ,7=2.4 Hz, 3H), 2.32 - 2.23 (m, HI), 2.10 - 1.99 (m, 1H), 1.82 - 1.68 (m, 3H).Intermediate 722-[(2S)-4-[7-(2,3-dimethylphenyl)-2-[[(2S -l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5 / / - pyrido[3,4-<7]pyrimidin-4-yl]piperazin-2-yl]acetonitrile

[0397] Step A: (25y2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2- rf(2>SVl-methvtoynOlidin-2- yl1methoxy1-6,8-dihvdro-5 / / -pyridor3,4-i]pyrimidin-4-yl1piperazine-l-carboxylate. A mixture of benzyl (2S,)-2-(cyanomethyl)-4-[2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-5, 6,7,8- tetrahydropyrido[3,4-<i]pyrimidin-4-yl]piperazine-l-carboxylate (1.22 g, 1.98 mmol, 1.0 eq ), 1 - bromo-2, 3 -dimethyl-benzene (1.10 g, 5.93 mmol, 802 uL, 3.0 eq), CS2CO3 (1.93 g, 5.93 mmol,3 eq), RuPhos (185 mg, 396 umol, 0.2 eq) and Pd2(dba)3(181 mg, 198 umol, 0.1 eq) in toluene (8 mL) was de-gassed and then heated to 90 °C for 12 hours under N2. Upon completion, the mixture was concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). The organic layers were dried over Na2S04filtered and concentrated under vacuum. The residue was purified by reversed-phase flash [water (0.1 % FA) / acetonitrile] The collected desired fractions were neutralized with saturated aqueous sodium bicarbonate and concentrated under vacuum to remove MeCN, and then extracted with EtOAc (3 x 50 mL). The organic layers were dried over Na2S04and concentrated under vacuum to give (2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2- [[(2A)-l-methylpyrrolidin-2- yl]methoxy]-6,8-dihydro-57 / -pyrido[3,4-c / ]pyrimidin-4-yl]piperazine~l-carboxylate (380 mg, 623 umol, 32 % yield, 100 % purity) as a yellow solid. LCMS [ESI, M+l]: 610.

[0398] Step B: 2-[(25r)-4-[7-(2,3-dimethylphenyl)-2-r[(25)-l-methylpyrrolidin-2-yl]methoxy]- 6.8-dihydiO- pyrido[3,4-finpyrimidin-4-yl1piperazin-2-yl1acetonitrile· NH3was bubbled into MeOH (20 mL) at -70 °C for 30 minutes. A solution of benzyl (25 -2-(cyanomethyl)-4-[7-(2,3- dimethylphenyl)-2-[[(2S l - methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5 / -pyrido[3,4- f]pyrimidin-4-yl]piperazme-l -carboxylate (380 mg, 623 umol, 1.0 eq) was added the abovesolution followed by Pd / C (200 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2several times. The reaction was stirred under H2(15 psi) at 25 °C for 1 hour. Upon completion, the catalyst was filtered and the filtrate was concentrated to give title compound 2-[(25)-4-[7-(2,3-dimethylphenyl)-2-[[(25)-l-methylpyrrolidin-2-yl]methoxy]- 6,8-dihydro-5 / / -pyrido[3,4-<7]pyrimidin-4-yl]piperazin-2-yl]acetonitrile (230 mg, 459 umol, 74% yield, 95% purity) as a yellow solid.

[0399] *H NMR (400 MHz, chloroform-d) d = 7.11 (t, J= 8.0 Hz, 1H), 6.96 (d, J= 8.0 Hz, 2H), 4.39 (dd, J= 4.8, 10.4 Hz, 1H), 4.14 (dd, J= 12, 9.6 Hz, 1H), 4.02 - 3.95 (m, 3H), 3.84 - 3.78 (m, 1H), 3.31 - 3.19 (m, 1H), 3.17 - 3.04 (m, 5H), 3.04 - 2.95 (m, 1H), 2.89 (dd, J= 9.2, 11.6 Hz, 1H), 2.76 - 2.62 (m, 3H), 2.58 - 2.50 (m, 2H), 2.48 (s, 3H), 2.30 (s, 3H), 2.29 - 2.23 (m, 4H), 2.12 - 2.00 (m, 1H), 1.89 - 1.76 (m, 3H).Intermediate 73Boc

[0400] ter / -butyl(25)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-[[(25)-l-methylpyrrolidin-2- yl]methoxy]-6,8-dihydiO-5T / -pyrido[3,4-<i]pyrimidin-4-yl]piperazine-l-carboxylate

[0401] Step A: / er / -butyl (25)-2-(cvanomethyl)-4-[7-(2,3-dimethylphenyl)-2-methylsulfanyl-6,8- dihydiO- pyrido[3,4-r / ]pyrimidin-4-yllpiperazine-l-carboxylate. A mixture of / ert-butyl (25)- 2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydiOpyrido[3,4-ii]pyrimidin-4-yl)piperazine- 1-carboxylate (1.60 g, 3.96 mmol, 1.0 eq), l-bromo-2, 3-dimethyl-benzene (1.61 g, 8.70 mmol, 1.18 mL, 2.20 eq), Pd2(dba)3(362 mg, 395 umol, 0.10 eq), RuPhos (369 mg, 791 umol, 0.20 eq) and Cs2C03(3.87 g, 1 1.9 mmol, 3.0 eq) in toluene (8.0 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 90 °C for 12 hrs under N2atmosphere. The organic solvent was washed with water (20.0 mL). The aqueous phase was extracted with ethylacetate (3 x 30.0 mL). Combine extracts were washed with brine (80.0 mL), dried with Na2S04the solvent was then removed under vacuum. The residue was purified by columnchromatography (Si02, Petroleum ether: Ethyl acetate=3 : 1 to Ethyl acetate : Methanol = 10 : 1). Compound / er / -butyl (2S -2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-methylsulfanyl- 6,8-dihydro-5 / / -pyrido[3,4-i / ]pyrimidin-4-yl]piperazine-l-carboxylate (900 mg, 1.59 mmol, 40% yield, 90% purity) was obtained as a yellow solid. LCMS [ESI, M+l]: 509.

[0402] ’H NMR (400 MPIz, Chloroform-d) d 7.1 1 (t, J= 15.6 Hz, 1H), 6.95(d, J= 8.0 Hz,2H), 4.63 (br s, 1H), 4.10 - 3.93 (m, 4PI), 3.89 (br d, J= 4.8 Hz, 1H), 3.27 (dd, J= 3.6 Hz, J= 13.6 Hz, lH),3.24 - 3.05 (m, 3H), 3.05 2.95 (m, 1H), 2.89 - 2.67 (m, 4H), 2.52 (s, 3H), 2.30 (s, 3H), 2.28 (s, 3H ), 1.52 (s, 9H).

[0403] Step B: / eH-butyl (2y)-2-(cvanomethyl)-4-[7-(2,3-dimethylphenyl)-2-methylsulfinyl-6,8- dihvdro-5 / / -pyrido[3,4-< / lpyrimidin-4-ynpiperazine-l-carboxylate. A mixture of / cr / -butyl (2S)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2-methylsulfanyl-6,8-dihydro-5 / / -pyrido[3,4- <i]pyrimidin-4-yl]piperazine-l-carboxylate (500 mg, 983 umol, 1.0 eq), 3- chlorobenzenecarboperoxoic acid (200 mg, 983 umol, 1.0 eq) in DCM (5.0 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 0 °C for 30 min under N2atmosphere. The organic solvent was washed with water (10.0 mL). The aqueous phase was extracted with ethyl acetate (3 x 20.0 mL). Combine extracts were washed with brine (50.0 mL), dried with Na2S04the solvent was then removed under vacuum. The residue was purified by column chromatography (Si02, Petroleum ether: Ethyl acetate=3 : 1 to Ethyl acetate :Methanol = 10 : 1). Compound tert- butyl (2S -2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2- methylsulfmyl-6,8- dihydro-57 / -pyrido[3,4-c / ]pyrimidin-4-yl]piperazine-l-carboxylate (450 mg, 793 umol, 81% yield, 93% purity) was obtained as a yellow solid. LCMS [ESI, M+l]:525.

[0404] Step C: fe / 7-butyl (2S,)-2-(cvanomethyl)-4-[7-(2,3-dimethylphenyl)-2-[[(2Sr)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-57 / -pyrido[3,4-<i]pyrimidin-4-yllpiperazine-l- carboxylate. A mixture of tert- butyl (2S)-2-(cyanomethyl)-4-[7-(2,3- dimethylphenyl)-2- methylsulfmyl-6,8-dihydro-5 / / -pyrido[3,4-<7]pyrimidin-4-yl]piperazine-l-carboxylate (800 mg,1.52 mmol, 1.0 eq), [(2S)-l-methylpyrrolidin-2-yl]methanol (369 mg, 3.20 mmol, 380 uL, 2.10 eq), / -BuONa (293 mg, 3.05 mmol, 2.0 eq) in toluene (10.0 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 0 °C for 30 min under N2atmosphere. Thereaction was quenched with water (20.0 mL). The crude mixture was extracted with ethyl acetate (3 x 30.0 mL). Combine extracts were washed with brine (80.0 mL), dried with Na2S04the solvent was then removed under vacuum. The residue was purified by columnchromatography (Si02, Petroleum ether: Ethyl acetate=5: 1 to Dichloromethane:Methanol=l0:l). Title compound / cr / -butyl (25)-2-(cyanomethyl)-4-[7-(2,3-dimethylphenyl)-2- [[(25)-l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-4- yl]piperazine-l-carboxylate (740 mg, 1.22 mmol, 80% yield, 95% purity) was obtained as a yellow solid. LCMS [ESI, M+l]: 576.

[0405] 1H NMR (400 MHz, Chloroform-d) d 7.10 (t, J = 15.2 Hz, 1H), 6.95 (d, J= 8.0 Hz, 2H), 4.61 (br s, 1H), 4.39 (dd, J= 4.8 Hz, J= 9.6 Hz,IH), 4.13 - 4.00 (m, 4H), 3.89 (br d, J= 12.4 Hz 1H), 3.27 - 3.13 (m, 3H), 3.13 - 2.95 (m, 3H), 2.87 - 2.65 (m, 5H), 2.49 (s, 3H), 2.30 (s, 3H), 2.27 (s, 3H ), 2.09 - 2.06 (m, 1 H), 2.06 - 2.04 (m, 1 H), 1.93 - 1.62 (m, 4H), 1.51 (s, 9H).EXAMPLE 1l-(4-(7-(3-hydroxynaphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-l- yl)prop-2-en-l -one

[0406] Step A: tert-butyl 4-(4-((benzyloxy)carbonyr)piperazin-l-yl)-5,8-dihvdiOpyrido[3,4- d] pyrimidine-7 (61P -carboxylate : In 2 mL of dimethyl acetamide were combined tert-butyl 4- chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.0 g, 3.7 mmol), triethylamine (1.0 mL, 7.4 mmol), and benzyl 1 -piperazinecarboxylate (0.86 mL, 4.4 mmol). The reaction vessel was sealed and the reaction mixture was heated to 90 °C with stirring. After 5 hours, the reaction was diluted with brine and extracted with methyl t-butyl ether. The combined organic layers were washed sequentially with saturated ammonium chloride and brine, dried over MgSCL, and concentrated under reduced pressure to a thick oil. The oil was chromatographed (RediSep®, 24 g) eluting withL l ethyl acetate / Hexanes to give tert-butyl 4-(4- ((benzyloxy)carbonyl)piperazin-l-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.3 g, 2.9 mmol, 77 % yield). ES+APCI MS m / z 454.2 [M+H]+.

[0407] Step B : Benzyl 4-(5,6,7,8-tetrahydropyrido[3.,4-dlpyrimidin-4-yl)piperazine-l- carboxylate: To a solution of tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-l -yl)-5,8-2065UB5TITUTE SHEET (RULE 26)dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.58 g, 3.484 mmol) in dichloromethane (1 1.61 mL, 3.484 mmol) was added trifluoroacetic acid (2.668 mL, 34.84 mmol) and the reaction was stirred at room temperature for 3 hours. The reaction was concentrated under vacuum and the residue was taken up in dichloromethane. The solution was washed with sequentially with 1M NaOH and brine, dried over Na2S04, filtered and concentrated under vacuum. The crude product was purified by column chromatography (Biotage Isolera, 24G Isco RediSep® Gold, 10 to 20% methanol / dichloromethane) to afford the product (1.1 g, 89%) as an off-white foam. ES+APCI MS m / z 354.2 [M+H]+.

[0408] Step C: benzyl 4-(7-(3-(methoxymethoxy)naphthalen-l-yl)-5,6,7,8-tetrahvdropyrido[3,4- d1pyrimidin-4-yl)piperazine-l-carboxylate: To a vial was addedtris(dibenzylideneacetone)dipalladium (0) (0.0069 g, 0.0075 mmol), racemic-2,2'- bis(diphenylphosphino)-l,T-binaphthyl (0.0096 g, 0.015 mmol) and toluene (0.62 mL, 0.19 mmol). Argon was bubbled through the mixture for 5 minutes and then the vial was capped and the mixture was heated to 100 °C for 15 minutes. The mixture was cooled to ambient temperature and then sodium tert-butoxide (0.036 g, 0.37 mmol) was added followed by 1- bromo-3-(methoxymethoxy)naphthalene (0.050 g, 0.19 mmol) and benzyl 4-(5,6,7,8- tetrahydiOpyrido[3,4-d]pyrimidin-4-yl)piperazine-l-carboxylate (0.13 g, 0.37 mmol). The vial was capped and the mixture heated to 100 °C for 20 hours. The mixture was cooled to ambient temperature, diluted with dichloromethane and filtered through GF / F paper. The filtrate was concentrated and purified by column chromatography (Biotage Isolera, 12G Isco RediSep®, 10- 50% ethyl acetate / dichloromethane) to afford the product (0.062 g, 61%) as an off-white foam. ES+APCI MS m / z 540.3 [M+H]+.

[0409] Step D : 7-(3-(methoxymethoxy)naphthalen-l-yl)-4-(piperazin-l-yl)-5,6,7,8- tetrahydrop yrido [ 3 ,4-d]pyrimidine : To a solution ofbenzyl 4-(7-(3-(methoxymethoxy)naphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine- 1 -carboxylate (0.061 g, 0.1 1 mmol) in ethanol (1.1 mL, 0.1 1 mmol) and tetrahydrofuran (1.1 mL, 0.1 1 mmol) was added palladium (0.024 g, 0.01 1 mmol) (Degussa Type, 10 wt.%, 50% FLO). An atmosphere of Lb was introduced into the reaction vessel by vacuum, and then the reaction mixture was maintained under an atmosphere of H2. The mixture was stirred at ambient temperature for 2.5 hours, then diluted with methanol and filtered through GF / F paper.The colorless filtrate was concentrated under vacuum with toluene to provide an off-white foam (0.048 g, 105%) that was used directly in the next step. ES+APCI MS m / z 406.2 [M+H]+.

[0410] Step E: l-(4-(7-(3-(methoxymethoxy)naphthalen-l-ylV5,6,7,8-tetrahydropyrido[3,4- d1pyrimidin-4-yl)piperazin- 1 -vBprop-2-en- 1 -one: To a suspension of 7-(3- (methoxymethoxy)naphthalen-l-yl)-4-(piperazin-l-yl)-5,6,7,8-tetrahydropyrido[3,4- djpyrimidine (0.046 g, 0.1 1 mmol) in dichloromethane (1.1 mL, 0.11 mmol) at ambient temperature was added acryloyl chloride (1.2 mL, 0.12 mmol) (freshly prepared 0.1 M solution in dichloromethane) followed by triethylamine (0.032 mL, 0.23 mmol). The reaction was stirred at ambient temperature for 1 hour. The mixture was concentrated and the product was purified by column chromatography (Biotage Isolera, 12G Isco RediSep®, ethyl acetate) to afford the product (0.042 g, 79%) as an off-white solid foam. ES+APCI MS m / z 460.2 [M+H]+.

[0411] Step F: l-(4-(7-(3-hvdroxynaphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4-dlpyrimidin-4- yDpiperazin- 1 -yl)prop-2-en- 1 -one: To a solution of l-(4-(7-(3-(methoxymethoxy)naphthalen-l- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-l-yl)prop-2-en-l-one (0.034 g, 0.074 mmol) in ethyl acetate (0.74 mL, 0.074 mmol) was added hydrochloric acid (5 to 6 N solution in 2-propanol (0.44 mL, 2.2 mmol). The mixture was stirred at ambient temperature for 5 hours. The mixture was diluted with ethyl acetate (10 mL), filtered through a polypropylene filter and the collected solid was washed with ethyl acetate and hexanes to provide the product as the HC1 salt. The impure material was treated with 1 mL of ammonium hydroxide / methanol to quench the acid and the mixture was concentrated. The residue was dissolved in 10% methanol / dichloromethane and purified by column chromatography (Biotage Isolera, 12G Isco RediSep®, 2 to 5% methanol / ethyl acetate) to afford the product (0.008 g, 25%) as an off-white solid. ES+APCI MS m / z 416.2 [M+PI]+.

[0412] 1H NMR (CD30D, 400 MHz) 6 8.49 (s, 1H), 8.07 (app d, J = 8.2 Hz, 1H), 7.61 (app d, J = 8.2 Hz, 1H), 7.35 (m, 1H), 7.25 (m, 1H), 6.80 (m, 3H), 6.23 (dd, J = 16.8, 1.6 Hz, 1H), 5.77 (dd, J = 10.6, 2.0 Hz, 1H), 4.22 (br s, 2H), 3.80 (app t, J = 4.7 Hz, 4H), 3.63 (br s, 4H), 3.35 (br s, 2H), 3.03 (br s, 2H).EXAMPLE 2l-(4-(7-(7-hydroxynaphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-l- yl)prop-2-en- 1 -one

[0413] Synthesized according to the method of Example 1, using 2-bromo-7- (methoxymethoxy)naphthalene in place of l-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m / z 416.1 [M+H]+.EXAMPLE 3l-(4-(7-(naphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-l-yl)prop-2- en-l-one

[0414] Synthesized according to the method of Example 1, using 1 -iodonaphthalene in place of l-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m / z 400.2 [M+H]+.EXAMPLE 4l -(4-(7-(2-fluoro-6-hydiOxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-l yl)prop-2-en- 1 -one

[0415] Synthesized according to the method of Example 1, using 2-bromo-l-fluoro~3- (methoxymethyl)benzene in place of l-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m / z 384.2 [M+H]+.EXAMPLE 5l-(4-(7-(2-fluoro-5-hydroxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-l- yl)prop-2-en- 1 -one

[0416] Synthesized according to the method of Example 1, using 2-bromo-l-fluoro-4- (methoxymethoxy)benzene in place of l-bromo-3-(methoxymethoxy)naphthalene in Step C. ES+APCI MS m / z 384.2 [M+H]+.EXAMPLE 6T(4-(7-(3-hydroxynaphthalen-l-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4- yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0417] Steps A-C: benzyl 4-(7-(3-(methoxymethoxy)naphthalen-l-vP-6-methyl-5,6,7,8- tetrahydropyrido[3.4-d1pyrimidin-4-yl)piperazine-l-carboxylate: Synthesized according to themethod of Example 1, Steps A-C, using tert-butyl 4-chloro-6-methyl-5,8-dihydropyrido[3,4- d]pyrimidine-7(6H)-carboxylate in place of 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine- 7(6H)-carboxylate in Step A. ES+APCI MS m / z 430.2 [M+H]+.

[0418] Step Dl : benzyl 4-(7-(3-hydroxynaphthalen-l -yl)-6-methyl-5,6,7,8- tetrahydropyrido G 3 ,4-d] pyrimidin-4-yl)nipcrazine- 1 -carboxylate : To a solution of benzyl 4-(7- (3-(methoxymethoxy)naphthalen-l-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4- yl)piperazine-l -carboxylate (0.05 g, 0.09 mmol) in isopropanol (10 mL) was added hydrogen chloride (5-6M in isopropanol) (0.02 mL, 0.09 mmol) and the reaction stirred at room temperature for 1 hour. The reaction was concentrated under vacuum and the concentrate was partitioned between ethyl acetate and water to convert the material to the free base. The combined organic layers were washed with brine, dried over MgS04and concentrated under vacuum to give benzyl 4-(7-(3-hydroxynaphthalen-l -yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazine-l -carboxylate (0.005 g, 0.010 mmol, 11% yield). ES+APCI MS m / z 510.3 [M+H]+.

[0419] Step D2: 4-(7-(3-hydroxynaphthalen-l-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin-l-ol: Prepared according to the method of Example 1, Step D.

[0420] Step E: l-(4-(7-(3-hydiOxynaphthalen-l-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin-l-yl)prop-2-en-l-one: Prepared according to the method ofExample 1, Step E.EXAMPLE 7l -(4-(7-(5-methyl-lH-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-l- yl)prop-2-en- 1 -one

[0421] Steps A-D: benzyl 4-(7-(5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-4- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-l-carboxylate: Synthesized according to General Scheme 1, Steps A-C, using 4-bromo-5 -methyl- 1 -((2- (trimethylsilyl)ethoxy)methyl)-lH-indazole in place of l-bromo-3- (methoxymethoxy)naphthalene in Step C

[0422] Step Dl : benzyl 4-(7-(5 -methyl- 1 I t-indazol-4-gG)- 5 ,6,7 , 8-tetrahvdropyridol 3 ,4- d | p y ri m i di n -4-y G) pi perazine- 1 -carboxylate: To a solution of benzyl 4-(7-(5-methyl-l-((2- (trimethylsilyl)ethoxy)methyl)-lEl-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4- yl)piperazine-l -carboxylate (0.16 g, 0.26 mmol) in dichloromethane (10 mL) was added 2,2,2- trifluoroacetic acid (0.89 g, 7.8 mmol) followed by anisole (0.028 g, 0.26 mmol), and the reaction was stirred at room temperature for 3 hours at room temperature. The reaction was concentrated under vacuum and the concentrated material was taken up in ethyl acetate and washed with basic brine. The combined organic layers were dried over MgS04and concentrated under vacuum. The crude material was chromatographed using 0 to 10%methanol / dichloromethane as the eluent to give benzyl 4-(7-(5-methyl-lH-indazol-4-yl)-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-l-carboxylate (0.05g, 38%). ES+APCI MS m / z 484.2 [M+H]+.

[0423] Step D2: 7-(5-methyl-lH-indazol-4-yl)-4-(piperazin-l-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidine: Prepared according to the method of Example 1, Step D.

[0424] Step E: l-(4-(7-(5-methyl-lEl-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4- yl)piperazin-l-yl)prop-2-en-l-one: Prepared according to the method of Example 1, Step E.EXAMPLE 8(S)-l -(4-(2-((l-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-l-yl)-5, 6,7,8- tetrahydropyrido [3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0425] Step A: tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-l-yl)-2-chloiO-5,8- dihydropyrido G 3 ,4-d]pyrimidine-7 ( 6HV carboxylate : Benzyl 1 -piperazinecarboxylate (1.268 mL, 6.575 mmol) and tert-Butyl 2,4-dichloro-5,6-dihydropyrido[3 4-d]pyrimidine-7(8H)- carboxylate (2 g, 6.575 mmol) were dissolved in dimethyl acetamide (10 mL) and treated with N-ethyl-N-isopropylpropan-2-amine (3.445 mL, 19.73 mmol). The reaction mixture was stirred at 85 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgS04,filtered and concentrated. The concentrate was purified by chromatography (CombiFlash®, 0%-50% ethyl acetate:Hexanes as the eluent to provide the product (2.69g, 83%). ES+APCI MS m / z 488.2, 490.2 [M+H]+.

[0426] Step B: tert-butyl (S)-4-(4-((benzyloxy)carbonyl)piperazin-l-yl)-2-((l- (dimethylamino)propan-2-yl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate: Tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-l-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (235 mg, 0.482 mmol), and (S)-l-(dimethylamino)propan-2-ol (497 mg, 4.82 mmol) were added to dioxane (0.5 mL) and heated to 100 °C for 3 days. The reaction was concentrated and the resulting residue was purified by silica gel (Biotage Isolera, 0-12% methanol in dichloromethane) to provide tert-butyl (S)-4-(4- ((benzyloxy)carbonyl)piperazin-l-yl)-2-((l-(dimethylamino)propan-2-yl)oxy)-5,8- dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (200 mg, 0.361 mmol, 74.9 % yield).ES+APCI MS m / z 555.3 [M+H]+.

[0427] Step C: benzyl (S)-4-(2-((l-(dimethylamino)propan-2-yl)oxy)-5, 6,7,8- tetrahydropyrido [3 ,4-dl pyrimidin-4-yl)piperazine- 1 -carboxylate : To a solution of tert-butyl (S)- 4-(4-((benzyloxy)carbonyl)piperazin-l-yl)-2-((l-(dimethylamino)propan-2-yl)oxy)-5,8- dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (200 mg, 0.3606 mmol) in dichloromethane (1202 pL, 0.3606 mmol) was added trifluoroacetic acid (828.3 pL, 10.82 mmol) and the reaction was stirred at room temperature for 3 hours. The reaction was concentrated under vacuum and the residue was taken up in dichloromethane. The solution was washed with 1M NaOH followed by brine and then dried overNa2S04, filtered and concentrated under vacuum. The crude product was purified by column chromatography (Biotage Isolera, 24G IscoRediSep®Gold, 10 to 20% methanol / dichloromethane) to afford the product as an off-white foam (0.135 g, 83%). ES+APCI MS m / z 455.2 [M+H]+.

[0428] Step D : benzyl (S)-4-(2-((l-(dimethylamino)propan-2-yl)oxy)-7-(3- (methoxymethoxy)naphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine- 1 -carboxylate: To a vial was added tris(dibenzylideneacetone)dipalladium (0) (21.8 mg, 0.0238 mmol), racemic-2,2'-Bis(diphenylphosphino)-l,T-binaphthyl (30.4 mg, 0.0488 mmol) and toluene (991 pL, 0.297 mmol). Argon was bubbled through the mixture for 5 minutes and then the vial was capped and the mixture was heated to 100 °C for 15 minutes. The mixture was cooled to ambient temperature and sodium tert-butoxide (57.2 mg, 0.595 mmol) was added followed by 3-(methoxymethoxy)naphthalen-l-yl trifluoromethanesulfonate (100 mg, 0.297 mmol) and benzyl (S)-4-(2-((l -(dimethylamino)propan-2-yl)oxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazine-l -carboxylate (135 mg, 0.297 mmol). The vial was capped and the mixture was heated to 100 °C for 18 hours. The mixture was cooled and concentrated. The crude material was purified by silica gel (Biotage Isolera, 0-1 1 % methanol / dichloromethane toprovide benzyl (S)-4-(2-((l-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine- 1-carboxylate (68 mg, 0.106 mmol, 35.7 % yield). ES+APCI MS m / z 641.3 [M+H]+.

[0429] Step E: (S)-2-((7-(3-(methoxymethoxy)naphthalen-l-yl)-4-(piperazin-l-yl)-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-l-amine: To a solution of benzyl (S)-4-(2-((l -(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-l -yl)- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-l-carboxylate (68 mg, 0.11 mmol) in ethanol (1061 pL, 0.1 1 mmol) and tetrahydrofuran (1061 pL, 0.11 mmol) was added Palladium (113 mg, 0.053 mmol) (Degussa Type, 10 wt.%, 50% H20). An atmosphere of H2was introduced by vacuum and then the reaction vessel was maintained under an atmosphere of H2. The mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with methanol and filtered through GF / F paper. The colorless filtrate was concentrated to provide (S)-2-((7-(3-(methoxymethoxy)naphthalen-l -yl)-4-(piperazin-l-yl)-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-l-amine (54 mg, 100 % yield) which was used in the next step without purification. ES+APCI MS m / z 507.3 [M+H]+.

[0430] Step F: (S)-l-(4-(2-((l-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen- 1 -yl)-5 ,6,7,8-tetrahydropyrido [3 ,4-d]pyrimidin-4-yl)piperazin- 1 - yl)prop-2-en-l-one: To a suspension of (S)-2-((7-(3-(methoxymethoxy)naphthalen-l-yl)-4- (piperazin-l-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-l- amine (54 mg, 0.1 1 mmol) in dichloromethane (1066 pL, 0.11 mmol) at ambient temperature was added acryloyl chloride (1279 pL, 0.13 mmol) (freshly prepared 0.1 M solution in DCM) followed by triethylamine (30 pL, 0.21 mmol). The reaction was stirred at ambient temperature for 20 minutes. The mixture was concentrated and the product was purified by column chromatography (Biotage Isolera, 12G Isco RediSep®, 0-15% methanol / dichloromethane) to afford (S)-l -(4-(2-((l-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-l - yl)-5,6,7,8-tetrahydiOpyrido[3,4-d]pyrimidin-4-yl)piperazin-l-yl)prop-2-en-l-one (51 mg,0.091 mmol, 85 % yield). ES+APCI MS m / z 561.3 [M+H]+.

[0431] Step G: l -(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-l-yl)-5, 6,7,8- tetrahydropyrido [3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one: (S)-l-(4-(2-((l - (dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-l -yl)-5, 6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-l-yl)prop-2-en-l-one (51 mg, 0.091 mmol) was added to a vial containing 350 mΐ , of methanol and a few drops of tetrahydrofuran and the reaction vial was capped. PIC1 (379 pL, 2.3 mmol) (6M aqueous) was added with stirring, and the mixture was heated to 55 °C for 3 hours. The reaction was cooled and concentrated under vacuum. A saturated bicarbonate solution was added and the reaction was extracted with 10% methanol in dichloromethane. The organic layers were combined and concentrated. The resulting residue was purified by silica gel (Biotage Isolera, 4-20% methanol indichloromethane with 1% concentrated ammonium chloride) to provide the title product (25.3 mg, 54%). ES+APCI MS m / z 517.2 [M+H]+.

[0432] Ή NMR (400 MHz, CDC13) 5 7.90 (d, 1H, J=8.3l4Hz), 7.54 (d, 1H, J=8.02l), 7.34 (m, 1H), 7.24 (m, 1H). 6.72 (m, 1H), 6.56-6.48 (m, 2H), 6.32 (dd, 1H, J=16.726, 1.858), 5.73 (dd, 1H, J=10.368, 1.858), 5.45 (m, 1H), 4.09-3.94 (m, 2H), 3.63 (bs, 2H), 3.47 (bs, 2H), 3.31 (m, 4H), 3.16 (bs, 2H), 2.84 (m, 1H), 2.60 (bs, 2H), 2.45 (m, 1H), 2.43 (s, 6H), 1.31 (d, 3H, J=6.162 Hz)EXAMPLE 9l-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0433] Synthesized according to the method of Example 8, using 2-(dimethylamino)ethan-l-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 503.2 [M+H]+.EXAMPLE 10l-(4-(2-(3-(dimethylamino)propoxy)-7-(3-hydroxynaphthalen-l-yl)-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en-l -one

[0434] Synthesized according to the method of Example 8, using 3-(dimethylamino)propan-l-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 517.3 [M+H]+.EXAMPLE 11l-(4-(2-((l-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8- tetrahydropyrido [3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0435] Synthesized according to the method of Example 8, using l-(dimethylamino)propan-2-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 517.3 [M+H]+.EXAMPLE 12l-(4-(7-(3-hydiOxynaphthaien-l-yl)-2-(4-meihyipiperazin-l-yI)-5,6,7,8-tetrahydropyrido[3,4 d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0436] Synthesized according to the method of Example 8, using 1 -methylpiperazine in place of(S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 514.3 [M+H]+.EXAMPLE 13l-(4-(2-(3-(dimethylamino)pyrrolidin-l-yl)-7-(3-hydroxynaphthalen-l-yl)-5, 6,7,8- tetrahydropyrido [3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0437] Synthesized according to the method of Example 8, using N,N-dimethylpyrrolidin-3 - amine in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 528.3[M+H]+.EXAMPLE 14(S)-l-(4-(7-(3-hydroxynaphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2- methylpiperazin- 1 -yl)prop-2-en- 1 -one

[0438] Synthesized according to the method of Example 8, using benzyl (S)-2- methylpiperazine-l-carboxylate in place of benzyl piperazine- 1 -carboxylate in Step A and using 2-(dimethylamino)ethan-l-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B.ES+APCI MS m / z 517.3 [M+H]+.EXAMPLE 15(R)-l-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-l -yl)-5,6,7,8- tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)-2-methylpiperazin- 1 -yl)prop-2-en- 1 -one

[0439] Synthesized according to the method of Example 8, substituting benzyl (R)-2- methylpiperazine- 1 -carboxylate for benzyl piperazine- 1 -carboxylate in Step A and 2- (dimethylamino)ethan- 1 -ol for (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 517.3 [M+H]+.EXAMPLE 16l-(6-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-l-one

[0440] Synthesized according to the method of Example 8, using benzyl 2,6- diazaspiro[3.3]heptane-2-carboxylate in place of benzyl piperazine- 1 -carboxylate in Step A and substituting 2-(dimethylamino)ethan-l-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 515.3 [M+H]+.EXAMPLE 17l-(4-(2-(4-(dimethylamino)piperidin-l-yl)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8- tetrahydropyrido [3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0441] Synthesized according to the method of Example 8, using N,N-dimethylpiperidin-4- amine in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 580.3[M+H]+.EXAMPLE 18l-(6-(2-((l-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-l-one

[0442] Synthesized according to the method of Example 8, using benzyl 2,6- diazaspiro[3.3]heptane-2-carboxylate in place of benzyl piperazine- 1 -carboxyl ate in Step A and substituting 1 -(dimethylamino)propan-2-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 529.3 [M+H]+.EXAMPLE 19(R)-l-(4-(2-((l-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8- tetrahydropyrido [3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0443] Synthesized according to the method of Example 8, using (R)-l-(dimethylamino)propan- 2-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 517.3[M+H]+.EXAMPLE 20l-(6-(2-(3-(dimethylamino)propoxy)-7-(3-hydroxynaphthalen-l-yl)-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-l-one

[0444] Synthesized according to the method of Example 8, using benzyl 2,6- diazaspiro[3.3]heptane-2-carboxylate in place of benzyl piperazine- 1 -carboxylate in Step A and substituting 3-(dimethylamino)propan-l-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 529.3 [M+H]+.EXAMPLE 211 -(4-(2-((4-(dimethylamino)butan-2-yl)oxy)-7-(3-hydroxynaphthalen-l-yl)-5, 6,7,8- tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0445] Synthesized according to the method of Example 8, using 4-(dimethylamino)butan-2-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 531.3 [M+H]+.EXAMPLE 221 -(4-(7-(3-hydroxynaphthalen- 1 -yl)-2-(( 1 -methylpiperidin-4-yl)oxy)-5, 6,7,8- tetrahydropyrido [3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0446] Synthesized according to the method of Example 8, using l-methylpiperidin-4-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 529.3 [M+H]+.EXAMPLE 23l-(4-(7-(3-hydroxynaphthalen-l-yl)-2-((l-methylpyrrolidin-3-yl)oxy)-5, 6,7,8- tetrahydropyrido [3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0447] Synthesized according to the method of Example 8, using l-methylpyrrolidin-3-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 515.3 [M+H]+.EXAMPLE 241 -(4-(2-((l -(dimethylamino)propan-2-yl)oxy)-7-(naphthalen- 1 -yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0448] Synthesized according to the method of Example 8, using l-(dimethylamino)propan-2-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B, using 1 -bromo naphthalene in place of3-(methoxymethoxy)naphthalen-l-yl trifluoromethanesulfonate in step D, and eliminating Step G. ES+APCI MS m / z 501.3 [M+H]+.EXAMPLE 25l -(4-(2-(3-(dimethylamino)propoxy)-7-(l-phenylethyl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0449] Synthesized according to the method of Example 8, using 3-(dimethylamino)propan-l -ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B, using ( 1 -bromoethyl)benzene in place of 3-(methoxymethoxy)naphthalen-l -yl trifluoromethanesulfonate in step D, and eliminating Step G. ES+APCI MS m / z 559.3 [M+H]+.EXAMPLE 26l-(4-(2-(4-(2-hydroxyethyl)piperazin-l-yl)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en-l -one

[0450] Synthesized according to the method of Example 8, using 2-(piperazin-l-yl)ethyl acetate in place of (S)-l-(dimethylamino)propan-2-ol in Step B. After Step D, the following saponification reaction was performed: Benzyl 4-(2-(4-(2-acetoxyethyl)piperazin-l-yl)-7-(3- (methoxymethoxy)naphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine- l-carboxylate was taken up in THF (5 mL) and 2 M LiOH (1 mL) was added. The mixture was stirred at ambient temperature for 24 hr. Saturated NH4Cl was added and the reaction was extracted with DCM. The combined organic layers were concentrated and the resulting residue was purified by silica gel (Biotage Isolera Gold, eluting with 0-10% MeOH in DCM) to provide benzyl 4-(2-(4-(2-hydroxyethyl)piperazin-l-yl)-7-(3-(methoxymethoxy)naphthalen-l-yl)- 5,6,7,8-tetrahydiOpyrido[3,4-d]pyrimidin-4-yl)piperazine~l-carboxylate. The remainder of the synthesis proceeded as in Example 8, step E. ES+APCI MS m / z 544.3 [M+H]+.EXAMPLE 27l-((S)-4-(2-(((R)-l-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-l -yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-l-yl)prop-2-en-l-one

[0451] Synthesized according to the method of Example 8, using benzyl (S)-3- methylpiperazine-1 -carboxylate in place of benzyl piperazine- 1 -carboxylate in Step A and using (R)-l-(dimethylamino)propan-2-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 531.3 [M+H]+.(S)-l-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazin-l-yl)prop-2-en-l -one

[0452] Synthesized according to the method of Example 8, using benzyl (S)-3- methylpiperazine-l-carboxylate in place of benzyl piperazine- 1 -carboxylate in Step A and using 2-(dimethylamino)ethan-l-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 517.2 [M+H]+.EXAMPLE 29l-(4-(7-(3-hydroxynaphthalen-l-yl)-2-(2-morpholinoethoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0453] Synthesized according to the method of Example 8, using 2-morpholinoethan-l-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APC1 MS m / z 545.2 [M+H]+.EXAMPLE 30l-(4-(7-(3-hydroxynaphthalen-l-yl)-2-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4- yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0454] Synthesized according to the method of Example 8, using morpholine in place of (S)-l- (dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 501.3 [M+H]+.EXAMPLE 31l _(4-(7-(3-hydiOxynaphthalen-l-yl)-2-(pyrrolidin-l-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0455] Synthesized according to the method of Example 8, using pyrrolidine in place of (S)-l- (dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 485.2 [M+H]+.EXAMPLE 32(R)-i-(4-(7-(3-hydroxynaphthaien-l-yl)-2-((l-(pyrrolidin-l-yl)propan-2-yl)oxy)-5, 6,7,8- tetrahydropyrido [3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0456] Synthesized according to the method of Example 8, using (R)-l-(pyrrolidin-l-yl)propan- 2-ol in place of (S)-l-(dimethylamino)propan-2-ol in Step B. ES+APCI MS m / z 543.4[M+H]+.EXAMPLE 33l-(4-(2-(2-(l,l -dioxidothiomorpholino)ethoxy)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-l-yl)prop-2-en-l-one trifluoroacetate

[0457] Step A: benzyl 4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(l,l-dioxo-l,4-thiazinan-4- yl)ethoxy]-6,8-dihydro-57 / -pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a mixture of benzyl 4-[7-(3-benzyloxy-l-naphthyl)-2-methylsulfmyl-6,8-dihydro-577-pyrido[3,4- d]pyrimidin-4-yl]piperazine-l-carboxylate (300 mg, 463.12 pmol, 1.00 eq) and 2-(l,l-dioxo- l ,4-thiazinan-4-yl)ethanol (166 mg, 926 pmol, 2.00 eq) in toluene (10.0 mL) was added NaOBu-t (133 mg, 1.39 mmol, 3.00 eq), BINAP (57.7 mg, 92.6 pmol, 0.20 eq), Pd2(dba)3 (42.4 mg, 46.3 pmol, 0.10 eq). The reaction mixture was stirred at 90 °C for 12 hours under N2. Thereaction mixture was filtered and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under vacuum. The residue was purified by reverse flashchromatography (40 % MeCN in water (0.1 % TFA) to give benzyl 4-[7-(3-benzyloxy-l - naphthyl)-2-[2-(l , 1 -dioxo- l ,4-thiazinan-4-yl)ethoxy]-6,8-dihydro-57 / -pyrido[3,4-d]pyrimidin- 4-yl]piperazine-l-carboxylate (230 mg, 301 pmol, 65.1 % yield) as a brown solid . ESI MS m / z763.5 [M+H]+.

[0458] Step B: 4-G2-G2-P , 1 -dioxo- 1 ,4-thiazinan-4-yl)ethoxyl-4-piperazin~ 1 -yl-6,8-dihydro-5 / / - pyridoD ,4-dlpyrimidin-7 -yllnaphthalen-2-ol : To a solution of benzyl 4-[7-(3-benzyloxy-l- naphthyl)-2-[2-(l ,1 -dioxo-1 ,4-thiazinan-4-yl)ethoxy]-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin- 4-yl]piperazine-l-carboxylate (190 mg, 249 pmol, 1.00 eq) in MeOH (10.0 mL) was added Pd / C (100 mg) under N2. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 40°C for 4 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 4-[2- [2-(l ,l-dioxo-l ,4-thiazinan-4-yl)ethoxy]-4-piperazin-l-yl-6,8-dihydro-57 / -pyrido[3,4- d]pyrimidin-7-yl]naphthalen-2-ol (90.0 mg, 167 pmol, 67.1 % yield) as a brown solid. ESI MS m / z 539.4 [M+H]+.

[0459] Step C: l-[4-[2-[2-(l , l -dioxo-l ,4-thiazinan-4-yl)ethoxy]-7-(3-hydroxy-l-naphthyl)-6,8- dihydro-57 / -pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one: To a solution of 4-[2- [2-( 1 , 1 -dioxo- 1 ,4-thiazinan-4-yl)ethoxy]-4-piperazin- 1 -yl-6,8-dihydro-5i / -pyrido [3 ,4- d]pyrimidin-7-yl]naphthalen-2-ol (90.0 mg, 167 pmol, 1.00 eq) and DIEA (64.8 mg, 501 pmol,87.5 pL, 3.00 eq) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (19.0 mg, 150 pmol, 0.90 eq) at -40 °C. The reaction mixture was stirred at -40 °C for 0.5 h. The reaction mixture was quenched with 1 mL of MeOH and concentrated under vacuum. The residue was purified by preparative HPLC column: Phenomenex Synergi C18 150*25*, 10 p; mobile phase: [water (0.1% TFA) -ACN]; B%: 12%-42%,1 1 min to give l -[4-[2-[2-(l ,l -dioxo-l ,4-thiazinan- 4-yl)ethoxy]-7-(3-hydiOxy-l -naphthyl)-6,8-dihydiO-5 / / -pyrido[3,4-d]pyrimidin-4-yl]piperazin- l-yl]prop-2-en-l -one trifluoroacetate (32.6 mg, 50.2 pmol, 30.0 % yield, 91.3 % purity) as a brown solid . ESI MS m / z 593.5 [M+H]+.EXAMPLE 34l-(4-(2-(3-(l,l-dioxidothiomorpholino)propoxy)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8- tetrahydropyrido [3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one trifluoroacetate

[0460] Synthesized according to the method of Example 33, using 3-(l,l-dioxo-l,4-thiazinan-4- yl)propan-l-ol in place of 2-(l,l-dioxo-l,4-thiazinan-4-yl)ethanol in Step A. ESI MS m / z 607.5 [M+H]+.EXAMPLE 35l-(4-(7-(3-hydroxynaphthalen-l-yl)-2-(4-morpholinobutoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin-l -yl)prop-2-en-l -one trifluoroacetate

[0461] Synthesized according to the method of Example 33, using 4-morpholinobutan-l-ol in place of 2-(l,l-dioxo-l,4-thiazinan-4-yl)ethanol in Step A. ESI MS m / z 573.4 [M+H]+.EXAMPLE 36(R)- 1 -(4-(2-(( 1 -(4-acetylpiperazin- 1 -yl)propan-2-yl)oxy)-7-(3 -hydroxynaphthalen- 1 -yl)-5 ,6,7,8- tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0462] Synthesized according to the method of Example 33, using l-[4-[(2 / ?)-2- hydroxypropyl]piperazin-l -yl]ethanone in place of 2-(l ,l-dioxo-l ,4-thiazinan-4-yl)ethanol in Step A. ESI MS m / z 600.6 [M+H]+.EXAMPLE 371 -(4-(2-(2-(4-acetylpiperazin- 1 -yl)ethoxy)-7-(3-hydroxynaphthalen- 1 -yl)-5,6,7,8- tetrahydropyrido [3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0463] Step A: benzyl 4-[2-[2-(4-acetylpiperazin-l -yl)ethoxy]-7-(3-benzyloxy-l -naphthyl)-6,8- dihydro-5 / / -pyrido[3,4-d]pyrimidin-4-yl]piperazine-l -carboxylate: To a solution of l-[4-(2- hydroxyethyl)piperazin-l -yl]ethanone (277 mg, 1.61 mmol, 2.60 eq) in THF (8.00 mL) was added NaH (49.4 mg, 1.23 mmol, 60 % purity, 2.00 eq) at 0°C.The reaction mixture was stirred at 0 °C for 15 minutes. To the mixture was added benzyl-4- [7-(3-benzyloxy-l -naphthyl)-2- methylsulfinyl-6,8-dihydiO-5 / / -pyrido[3,4-d]pyrimidin-4-yl]piperazine-l -carboxylate (400 mg,618 mihoΐ, 1.00 eq) in THF (2.00 mL). The reaction mixture was stirred at 0 °C for 20 minutes. The reaction mixture was quenched with saturated NH4Cl (6 mL) and water (6 mL). The reaction mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over Na2S04and concentrated under vacuum to give benzyl 4- [2- [2-(4-acetylpiperazin- 1 -yl)ethoxy] -7-(3 -benzyloxy- 1 -naphthyl)-6 , 8-dihydro- 5 H- pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (450 mg, 534 pmol, 86.5 % yield, 89.7 % purity) as a brown solid. ESI MS m / z 756.3 [M+H]+.

[0464] Step B: l-[4-[2-[[7-(3-hydroxy-l-naphthyl)-4-piperazin-l-yl-6,8-dihydro-57 / -pyrido[3,4- d]pyrimidin-2-yl]oxy]ethyl]piperazin-l-yl]ethanone: To a solution of benzyl 4-[2-[2-(4- acctylpiperazin-1 -yl)ethoxy]-7-(3 -benzyloxy- 1 -naphthyl)-6,8-dihydro-5 / 7-pyrido[3,4- d]pyrimidin-4-yl]piperazine-l-carboxylate (200 mg, 264 pmol, 1.00 eq) in THF (10.0 mL) was added Pd / C (100 mg, 10 % purity) under N2. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 40 °C for 12 hours. The reaction mixture was filtered and the filter cake was washed with THF (3 x 5 mL). The filtrate was concentrated under vacuum to give l-[4-[2-[[7-(3-hydroxy-l-naphthyl)-4- piperazin-l -yl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-2-yl]oxy]ethyl]piperazin-l -yl]ethanone (80.0 mg, 150 pmol, 56.9 % yield) as a brown solid.

[0465] Step C: l -[4-[2-[2-(4-acetylpiperazin-l-yl)ethoxy]-7-(3-hydroxy-l -naphthyl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l -one: To a solution of l-[4- [2-[[7-(3-hydroxy-l-naphthyl)-4-piperazin-l -yl-6,8-dihydiO-57 / -pyrido[3,4-d]pyrimidin-2- yl]oxy]ethyl]piperazin-l -yl]ethanone (80.0 mg, 150 mihoΐ, 1.00 eq) and DIEA (58.3 mg, 451 pmol, 78.8 pL, 3.00 eq) in DCM (2.00 mL) was added prop-2-enoyl prop-2-enoate (14.2 mg,1 13 pmol, 0.75 eq) at - 40 °C for 0.5 h. The reaction mixture was quenched with MeOH (1 mL) and diluted by DCM (20 mL) next washed with water (5 mL). The combined organic layers were washed with brine (5 mL), dried over Na2S04and concentrated under vacuum. The reaction mixture was purified by preparative HPLC : Phenomenex Gemini 150*25mm*, 10 m; mobile phase: [water (0.05% ammonia hydroxide v / v) - ACN]; B%: 30%-55%, 10 min to give l -[4-[2-[2-(4-acetylpiperazin-l -yl)ethoxy]-7-(3-hydroxy- l -naphthyl)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l -one (13.8 mg, 23.3 mihoΐ, 15.5 % yield, 98.7 % purity) as a yellow solid. ESI MS m / z 586.3 [M+PI]+.EXAMPLE 38l-(4-(7-(3-hydroxynaphthalen-l-yl)-2-(3-(piperidin-l-yl)propoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0466] Synthesized according to the method of Example 37, using 3-(l-piperidyl)propan-l-ol in place of l-[4-(2-hydroxyethyl)piperazin-l-yl]ethanone in Step A. ESI MS m / z 557.5 [M+H]+.EXAMPLE 39l-(4-(7-(3-hydiOxynaphthalen-l-yl)-2-(3-(pyrrolidin-l-yl)propoxy)-5,6,7,8-tetrahydiOpyrido[3,4- d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0467] Synthesized according to the method of Example 37, using 3-pyrrolidin-l-ylpropan-l-ol in place of l-[4-(2-hydroxyethyl)piperazin-l-yl]ethanone in Step A. ESI MS m / z 543.3[M+H]+.EXAMPLE 40l-(4-(2-(4-(dimethylamino)butoxy)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0468] Synthesized according to the method of Example 37, using 4-(dimethylamino)butan-l-ol in place of l-[4-(2-hydroxyethyl)piperazin-l-yl]ethanone in Step A. ESI MS m / z 531.4[M+H]+.EXAMPLE 41l-(4-(7-(3-cyclopropyl-5-hydroxyphenyl)-2-(3-morpholinopropoxy)-5,6,7,8- tetrahydiOpyrido[3,4-d]pyrimidin-4-yl)piperazin-l-yl)prop-2-en-l-one trifluoroacetate

[0469] Step A: 4-[7-(3-benzyloxy-5-cyclopropyl-phenyl)-2-(3- morpholinopropoxy)-6,8- dihydro-57 / -pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a mixture of benzyl 4-[2- (3-morpholinopiOpoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (400 mg, 805 pmol, 1.00 eq) and l-benzyloxy-3-bromo-5 -cyclopropyl-benzene (268 mg, 886 pmol, 1.10 eq) in toluene (10.0 mL) was added 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (RuPhos) (75.2 mg, 161 pmol, 0.20 eq ), Pd2(dba)3 (1 1 1 mg, 121 pmol,0.15 eq ) and CS2CO3(656 mg, 2.01 mmol, 2.50 eq). The reaction mixture was stirred at 90 °C for 12 hours under N2. The mixture was added to water (15 mL) and extracted with DCM (2 x 15 mL). The combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified by chromatography (S1O2, Petroleum ether / Ethyl acetate = 3:1 toDichloromethane: Methanol = 10:1) to give benzyl 4-[7-(3-benzyloxy-5-cyclopropyl-phenyl)-2- (3- morpholinopiOpoxy)-6,8-dihydro-5 / 7-pyrido[3,4-djpyrimidin-4-yl]piperazine-l-carboxylatc (170 mg, 230 pmol, 28.5 % yield, 97.2 % purity) as brown oil. ESI MS m / z 719.6 [M+H]+.

[0470] Step B: 3-cvclo -5- f2-(3-morpholinopiOpoxy)-4- piperazin- 1 -yl-6,8-dihydro-PVrido[3,4-d1pyrimidin-7-yl1phenol To a mixture of benzyl 4-[7-(3-benzyloxy-5-cyclopropyl- phenyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-4-yl]piperazine-l- carboxylate (150 mg, 209 pmol, 1.00 eq) in MeOH (10.0 mL) was added Pd / C (150 mg, 10 % purity) and CH3COOH (25.1 mg, 417.3 pmol, 23.9 pL, 2.00 eq). The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 Psi) at 40 °C for 2 hours. The reaction mixture was filtered through Celite® and the filtrate was concentrated. The product 3-cyclopropyl-5-[2-(3-morpholinopropoxy)-4- piperazin- l-yl- 6,8-dihydro-5T / -pyrido[3,4-d]pyrimidin-7-yl]phenol diacetate (80.0 mg, 130 pmol, 62.4 % yield) was obtained as yellow solid. ESI MS m / z 495.2 [M+H]+.

[0471] Step C: l-[4-[7-(3-cyclopropyl-5-hydroxy-phenyl) -2-(3-morpholinopropoxy)-6,8- dihydro-57 / -pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one To a mixture of 3- cyclopropyl-5-[2-(3-morpholinopropoxy)-4-piperazin-l-yl-6,8-dihydro-5 / 7-pyrido[3,4- d]pyrimidin-7-yl]phenol diacetate (80.0 mg, 130 pmol, 1.00 eq) in DCM (2.00 mL) was added DIEA (168 mg, 1.30 mmol, 227 pL, 10.0 eq) and prop-2-enoyl prop-2-enoate (13.1 mg, 104 pmol, 0.80 eq) at -78 °C, the reaction mixture was stirred at -78 °C for 0.5 hour. The reaction mixture was quenched with MeOH (2 eq, 10 mg), then concentrated. The residue was purified by preparative HPLC (Instrument: GX-K; Column: Phenomenex Synergi C18 150*25*, 10 p; Conditions: water (0.1 % TFA)-ACN; Begin B: 8; End B: 38; Gradient Time (min): 11 ; 100% B Hold Time (min): 2; FlowRate (mL / min): 25). The isolated product was concentrated by lyophilization. The product l-[4-[7-(3-cyclopropyl-5-hydroxy-phenyl) -2-(3- morpholinopiOpoxy)-6,8-dihydiO-5 / 7-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]piOp-2-en-l-one trifluoroacetate (21.5 mg, 31.1 pmol, 23.9 % yield, 95.8 % purity) was obtained as yellow solid. ESI MS m / z 549.5 [M+H]+.EXAMPLE 42l-(4-(7-(2-fluoro-5-hydroxyphenyl)-2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0472] Synthesized according to the method of Example 41, using 4-(benzyloxy)-2-bromo-l- fluorobenzene in place of l-benzyloxy-3-bromo-5-cyclopropyl-benzene in Step A. ESI MS m / z 527.4 [M+H]+.EXAMPLE 43l-(4-(7-(3-hydroxy-6-methylnaphthalen-l-yl)-2-(3-morpholinopropoxy)-5,6,7,8- tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0473] Step A: benzyl 4-[7-(3-methoxy-6-methyl-l-naphthyl)-2- (3-morpholinopropoxy)-6,8- dihydro-5 / / -pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: A mixture of benzyl 4-[2-(3- morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate(500 mg, 1.01 mmol, 1.00 eq), (3-methoxy-6-methyl-l-naphthyl)trifluoiOmethanesulfonate (483 mg, 1.51 mmol, 1.50 eq), Cs2C03(820 mg, 2.52 mmol, 2.50 eq), 2-dicyclohexylphosphino- 2',6'-diisopropoxybiphenyl (RuPhos) (93.9 mg, 201.3 pmol, 0.20 eq) and Pd2(dba)3(92.2 mg, 100 pmol, 0.10 eq) in toluene (3.00 mL) was stirred at 90 °C for 10 hours. The mixture was diluted with ethyl acetate (50.0 mL). The precipitate was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by reversed phase columnchromatography over silica gel (0.1% TFA water / acetonitrile). The desired fractions were combined and basified with saturated aqueous sodium bicarbonate (2.00 mL), then concentrated under vacuum. The residue was extracted with ethyl acetate (2 x 100 mL). The combined extracts were washed with brine (1c100 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give benzyl 4-[7-(3-methoxy-6-methyl-l-naphthyl)-2- (3- morpholinopropoxy)-6,8-dihydiO-5 / / -pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (400. mg, 599 pmol, 59.4 % yield, 100 % purity) as a yellow solid. ESI MS m / z 667.6 [M+H]+.

[0474] Step B: 4-[3-[[7-(3-methoxy-6-methyl-l-naphthyl)-4-piperazin-l-yl-6,8-dihydro-5i7- pyrido[3,4-d]pyrimidin-2-yl] To a solution of benzyl 4-[7-(3-methoxy-6-methyl-l -naphthyl) -2-(3-morpholinopropoxy)-6.8-dihydro-5 / 7-pyrido[3,4-d]pynmidin-4- yl]piperazine-l-carboxylate (370 mg, 554 pmol, 1.00 eq) in MeOH (10.0 mL) was added Pd-C ( 100 mg, 10 % purity) and AcOH (66.6 mg, 1.11 mmol, 2.00 eq) under N2. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 40 °C for 2 hours. The reaction mixture was filtered and concentrated in vacuum to provide 4-[3-[[7-(3-methoxy-6-methyl-l-naphthyl)-4-piperazin-l-yl-6,8-dihydro-5i7- pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine (295 mg, 553 pmol, 99.8 % yield) as a yellow solid which was used directly in the next step without purification. ESI MS m / z 533.6 [M+H]+

[0475] Step C: l-[4-[7-(3-methoxy-6-methyl-l-naphthyl)-2-(3-morpholinopropoxy) -6,8- dihydiO-5 / / -pyrido[3,4-d]pyrimidin-4-yl]piperazin-l -yl]prop-2-en-l-one: To a mixture of prop- 2-enoyl prop-2-enoate (56.8 mg, 450 pmol, 0.80 eq) and DIEA (727 mg, 5.63 mmol, 983 pL, 10.0 eq) in DCM (2.00 mL) was added a solution of 4-[3-[[7-(3-methoxy-6-methyl-l-naphthyl)- 4-piperazin-l-yl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine (300 mg, 563 pmol, 1.00 eq) DCM (1.00 mL) at - 40°C under a nitrogen atmosphere. The mixture wasstirred for 1 hour. The reaction mixture was quenched by addition of MeOH (50 pL) at -40°C, diluted with water (10.0 mL), extracted with DCM(10.0 mL), dried over Na2S04, filtered and concentrated under reduced pressure to provide l-[4-[7-(3-methoxy-6-methyl-l-naphthyl)-2-(3- morpholinopropoxy) -6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l- one (270 mg, 460 pmol, 81.7 % yield) ESI MS m / z 587.6 [M+H]+.

[0476] Step D: l-[4-[7-(3-hydroxy-6-methyl-l -naphthyl) -2-(3-morpholinopropoxy)-6,8- dihydro-57 / -pyrido[3,4-d]pyrimidin-4-yl]piperazm-l-yl]prop-2-en-l-one: To a solution of 1-14- [7-(3-methoxy-6-methyl-l-naphthyl)-2- (3-morpholinopropoxy)-6,8-dihydro-5 / / -pyrido[3,4- d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one (100 mg, 170 pmol, 1.00 eq) in DCM (3.00 mL) was added BBr3(213 mg, 852 pmol, 82.1 pL, 5.00 eq) at -78 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was cooled to -78 °C and diluted with DCM (20.0 mL), quenched by addition of saturated sodium bicarbonate solution (5.00 mL) and stirred at -78 °C for 10 mins, then warmed to 0 °C. The mixture was extracted with DCM (2 x 15.0 mL), washed with brine (1 x 20.0 mL), dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by preparative LIPLC (column: Phenomenex Gemini Cl 8 250*50 mm*, 10 p; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 27%-57%, 12 min) to provide l -[4-[7-(3-hydroxy-6-methyl-l-naphthyl)-2-(3-morpholinopiOpoxy)-6,8-dihydro-57 - pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l -one (1 1.0 mg, 18.6 pmol, 10.9 % yield, 97.0 % purity) as a brown solid. ESI MS m / z 573.6 [M+H]+.EXAMPLE 44l -(4-(7-(5-methyl-l H-indazol-4-yl)-2-(3-morpholinopiOpoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0477] Step A: benzyl 4-[7-[5-methyl-l-(2-trimethylsilylethoxymethyl)indazol-4-yl]- 2-(3- morpholinopropoxy)-6,8-dihydro-5i7-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l -carboxylate: A mixture of benzyl 4-[2-(3-morpholinopropoxy)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4- yl]piperazine-l-carboxylate (500 mg, 1.01 mmol, 1.00 eq), 2-[(4-bromo-5-methyl-indazol-l- yl)methoxy] ethyl-trimethylsilane (448 mg, 1.31 mmol, 1.30 eq), CS2CO3(822 mg, 2.53 mmol, 2.50 eq), Pd2(dba)3(138 mg, 151 pmol, 0.15 eq) and 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (RuPhos) (94.3 mg, 202 pmol, 0.20 eq) in toluene (20.0 mL) was degassed and purged with nitrogen 3 times, and stirred at 90 °C for 10 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3 x 50.0 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by reversed phase HPLC (0.1% TFA water / acetonitrile) to provide benzyl 4-[7-[5-methyl-l-(2- trimethylsilylethoxymethyl)indazol-4-yl]- 2-(3-morpholinopropoxy)-6,8-dihydro-57 / - pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (420 mg, 554 pmol, 54.9 % yield) as a yellow oil. ESI MS m / z 757.6 [M+H]+.

[0478] Step B: / er / -butyl 4-[7-[5-methyl-l-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3- morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a solution of benzyl 4-[7-[5-methyl-l-(2-trimethylsilylethoxymethyl) indazol-4-yl]-2-(3- UK)rpholinopropoxy)-6, 8-dihydro-5 / / -pyrido [3, 4-d]pyrimidin-4-yr| piperazine- l-carboxylate (370 mg, 488 pmol, 1.00 eq) in MeOH (10.0 mL) was added triethylamine (98.9 mg, 977 pmol, 135 pL, 2.00 eq), Pd / C(100 mg, 10 % purity) and / er / - butox y carbo n y 1 tert- butyl carbonate (213 mg, 977 pmol, 224 pL, 2.00 eq) under N2. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 40 °C for 2 hours. The reaction mixture was filtrated and concentrated under vacuum. The residue was purified by column chromatography (Si02, DCM / MeOH = 1 :0 to 10:1) to provide tert- butyl 4- [7-[5-methyl-l-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (340 mg, 470 pmol, 96.2 % yield) as a brown oil. ESI MS m / z 723.5 [M+H]+.

[0479] Step C: 4-[3-[[7-(5-methyl- indazol-4-yl) -4-piperazin-l -yl-6,8-dihydro-PVrido[3,4-dlpyrimidin-2-yl]oxy1piOPyl1morpholine trifluoroacetate : To a solution of / er / -butyl4-[7-[5-methyl-l- (2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-morpholinopropoxy)-6,8- dihydro-5 / 7-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (150 mg, 207 pmol, 1.00 eq ) in DCM (500 pL) was added TFA (354 mg, 3.11 mmol, 230 pL, 15.0 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuum to provide 4-[3- [[7-(5-methyl-l / / -indazol-4-yl) -4-piperazin-l-yl-6,8-dihydro-577-pyrido[3,4-d]pyrimidin-2- yl]oxy]propyl]morpholine trifluoroacetate (125 mg, 206 pmol, 99.3 % yield) as a brown oil and used directly in the next step without purification. ESI MS m / z 493.4 [M+H]+.

[0480] Step D l-[4-[7-(5-methyl-lf / -indazol-4-yl) -2-(3-morpholinopropoxy)-6,8-dihydro-577- pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one : To a mixture of 4-[3-[[7-(5- methyl-177-indazol-4-yl)-4-piperazin -l-yl-6,8-dihydro-5 / 7-pyrido[3,4-d]pyrimidin-2- yl]oxy]propyl]morpholine trifluoroacetate (120 mg, 197 pmol, 1.00 eq , TFA) and DIEA (255 mg, 1.98 mmol, 345 pL, 10.0 eq) in dichloromethane (2.00 mL) was added a solution of prop-2- enoyl prop-2-enoate (19.9 mg, 158 pmol, 0.80 eq) dichloromethane (1.00 mL) at -40°C under nitrogen atmosphere. The mixture was stirred for 1 hour. The reaction mixture was quenched by addition of MeOFI (50.0 pL) at -40°C, diluted with water (10.0 mL), extracted withdichloromethane (10.0 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini 150*25mm*, 10 p; mobile phase: [water (0.05% ammonia hydroxide v / v) - ACN]; B%: 30%- 60%, 10 min) to provide 1- [4- [7-(5 -methyl- l / 7-indazol-4-yl) -2-(3-morpholinopropoxy)-6,8- dihydiO-5 / / -pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one (19.0 mg, 34.4 pmol, 17.4 % yield, 99.0 % purity) as a white solid. ESI MS m / z 547.5 [M+H]+.EXAMPLE 45l-((lR,5S)-3-(2-((l-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-l-one

[0481] Step A: tert- butyl 3-(7-benzyl-2-chloiO-6,8-dihvdro-5 / / -pyrido[3.,4-dlpyrimidin-4-yl)-3.8-diazabicvclo[3.2.l1octane-8-carboxylate: To a mixture of 7 -benzyl-2, 4-dichloro-6, 8- dihydro-5 / / -pyrido[3,4-d]pyrimidine (920 mg, 3.13 mmol, 1.00 eq) and tert- butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (677 mg, 3.19 mmol, 1.02 eq) in DMSO (18.0 mL) was added DIEA (1.21 g, 9.39 mmol, 1.64 mL, 3.00 eq). The reaction mixture was stirred at 60 °C for 1 hour. The mixture was diluted with extracted with EtOAc (3 x 20 mL), washed with water (10 mL), IN HC1 (5 mL), NaHC03(15 mL), and brine (15 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under vacuum to give / er / -butyl 3-(7- benzyl-2-chloro-6,8-dihydro-57 / -pyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.30 g, 2.41 mmol, 76.9 % yield, 87.0 % purity) as a brown oil which was used directly in the next step without further purification. ESI MS m / z 470.2 [M+H]+.

[0482] Step B: / <?r / -butyl 3-[7-benzyl-2-[2-(dimethylamino)-l-methyl-ethoxy]-6,8-dihydro-5 / / - pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of 1- (dimethylamino)propan-2-ol (857 mg, 8.31 mmol, 942 pL, 3.00 eq) in THF (40.0 mL) was added NaH (222 mg, 5.54 mmol, 60.0 % purity, 2.00 eq) at 15 °C under N2. After stirring at 15 °C for 0.5 hour, tert- butyl 3-(7-benzyl-2-chloiO-6,8-dihydro-5i7-pyrido[3,4-d]pyrimidin-4-yl)-3.8-diazabicyclo[3.2.1]octane-8-carboxylate (1.30 g, 2.77 mmol, 1.00 eq) was added. The mixture was stirred at 100 °C for 12 hours in a sealed tube. The reaction was slowly quenched with water (3 mL) and then concentrated under vacuum. The residue was purified by column chromatography (DCM / MeOH 60:1 to 10: 1) to give / 7-butyl 3-[7-benzyl-2-[2- (dimethylamino)-l -methyl-ethoxy]-6,8-dihydiO-57 / -pyrido[3,4-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 1.07 mmol, 38.8 % yield, 82.4 % purity) as a yellow oil.

[0483] Step C: tert- butyl 3-[2-[2-(dimethylamino)-l-methyl-ethoxy]-5,6,7,8- tetrahydiOpyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate : To a solution of tert- butyl 3-[7-benzyl-2-[2-(dimethylamino)-l-methyl-ethoxy]-6,8-dihydro-5 / / - pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 1.30 mmol, 1.00 eq) in MeOH (30.0 mL) was added Pd / C (200 mg) under N2. The suspension was degassedunder vacuum and purged with hydrogen 4 times. The mixture was stirred under hydrogen (50 psi) at 40 °C for 12 hours. The mixture was concentrated under vacuum. The residue was purified by column chromatography (DCM / MeOH 50:1 to 5:1) to give / er / -butyl 3-[2-[2- (dimethylamino)-l-methyl-ethoxy]-5,6,7,8-tetrahydiOpyrido[3,4-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.l]octane-8-carboxylate (500 mg, 952 pmol, 73.2 % yield, 85.0 % purity) as a yellow oil.

[0484] Step D: / er / -butyl 3-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)-l-methyl- ethoxy]-6,8-dihydro-5 / / -pyrido|3,4-d jpynmidin-4-ylj-3,8-diazabicyclo[3.2.1 joctane-8- carboxylate: Pd2(dba)3(84.1 mg, 91.8 pmol, 0.10 eq) was added to a solution of / er / -butyl 3-[2- [2-(dimethylamino)-l-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (410 mg, 918 pmol, 1.00 eq), 3-benzyloxy-l-bromo- naphthalene (293 mg, 936 pmol, 1.02 eq), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (85.7 mg, 184 pmol, 0.20 eq) and Cs2C03(897 mg, 2.75 mmol, 3.00 eq) in dioxane (9.00 mL). The reaction mixture was stirred at 100 °C for 7 hours under N2and thenconcentrated under vacuum. The residue was diluted with water (5 mL) and extracted with DCM (2 x 20 mL). The organic layers were dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by column chromatography (DCM / MeOH 100:1 to 20:1) to give tert-buiy\ 3-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)-l-methyl-ethoxy]-6,8- dihydro-5 / / -pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (317 mg, 441 pmol, 48.1 % yield, 94.5 % purity) as a yellow oil. ESI MS m / z 679.2 [M+H]+.

[0485] Step E: tert- butyl 3-[2-[2-(dimethylamino)-l-methyl-ethoxy]-7-(3-hydroxy-l-naphthyl)-6.8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of teri-butyl 3-[7-(3-benzyloxy- 1 -naphthyl)-2-[2-(climethylamino)- 1 -lncthyl-ethoxy]-6.8-dihydro-57 / -pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (340 mg, 501 pmol, 1.00 eq) in MeOLI (6.80 mL) was added Pd / C (120 mg). The suspension was degassed under vacuum and purged with hydrogen 4 times. The mixture was stirred under hydrogen (15 psi) at 40 °C for 1.5 hours. The mixture was concentrated under vacuum to give / er / -butyl 3-[2-[2-(dimethylamino)-l-methyl-ethoxy]-7-(3-hydroxy-l-naphthyl)-6, 8-dihydro- 57 / -pyrido[3,4-d]pyrimidin-4-yrj-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (210 mg, 316 pmol, 63.1 % yield, 88.6 % purity) as a yellow solid which was used directly in the next stepwithout further purification. ESI MS m / z 589.3 [M+H]+.Step F: 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[2-(dimethylamino)-l -methyl-ethoxy]-6,8- di hydro-5 / / -pyrido [3, 4-d]pyrimidin-7-yl]naphthalen-2-ol trifluoroacetate : To a solution of tert- butyl 3 - [2- [2-(dimethy lamino)- 1 -methyl-ethoxy] -7-(3 -hydroxy- 1 -naphthyl)-6,8-dihydro-5 / 7- pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (180 mg, 306 pmol, 1.00 eq ) in DCM (230 pL) was added TFA (349 mg, 3.06 mmol, 226 pL, 10.0 eq). The reaction mixture was stirred at 18 °C for 0.5 hour. The mixture was concentrated under vacuum to give 4- [4-(3 , 8 -diazabicyclo [3.2.1] octan-3 -yl)-2- [2-(dimethylamino)- 1 -methyl-ethoxy] -6, 8-dihy dro- 5 / 7-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol trifluoroacetate (528 mg, crude) as a red oil which was used directly in the next step without further purification. ESI MS m / z 489.2[M+H]+.

[0486] Step G: l-[3-[2-[2-(dimethylamino)-l-methyl-ethoxy]-7-(3-hydroxy-l-naphthyl)-6,8- dihydiO-577-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]prop-2-en-l-one:To a solution of 4-[4-(3,8-diazabicyclo[3.2. l]octan-3-yl)-2-[2-(dimethylamino)-l-methyl- ethoxy]-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol trifluoroacetate (149 mg, 306 pmol, 1.00 eq) and DIEA (1.36 g, 10.5 mmol, 1.84 mL, 34.5 eq) in DCM (1.50 mL) was added prop-2-enoyl prop-2-enoate (30.9 mg, 245 pmol, 0.80 eq) dropwise at - 50 °C. The mixture was stirred at -40 and then -20 °C for 30 minutes. The reaction was quenched with MeOFI (19.6 mg) and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOFI 7: 1) to give l-[3-[2-[2-(dimethylamino)-l-methyl-ethoxy]-7-(3-hydroxy-l- naphthyl)-6,8-dihydro-5 / T-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]prop- 2-en-l-one (18.9 mg, 32.8 pmol, 10.7 % yield, 94.3 % purity) as a yellow solid. ESI MS m / z 543.3 [M+H]+.EXAMPLE 46l-((lR,5S)-8-(2-((l-(dimethylamino)propan-2-yl)oxy)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8- tetrahydropyrido [3 ,4-d]pyrimidin-4-yl)-3 , 8 -diazabicyclo [3.2.1 ] octan-3 -yl)prop-2-en- 1 -one

[0487] Synthesized according to the method of Example 4, using tert-butyl (lR,5S)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate in place tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate in Step A. ESI MS m / z 543.4 [M+H]+.EXAMPLE 47l-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-l-yl)-8-methyl-5,6,7,8- tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0488] Step A: ethyl 2-(benzylamino )Dronanoate: To a solution of ethyl 2-bromopropanoate (30.0 g, 165 mmol, 21.6 mL, 1.00 eq), BnNH2(23.1 g, 215 mmol, 23.6 mL, 1.30 eq) in MeCN (600 mL) was added K2CO3 (45.8 g, 331 mmol, 2.00 eq). The mixture was stirred at 80 °C for 2 hour. The reaction mixture was filtered and the filter cake was washed with DCM (300 mL). The filtrated was concentrated under vacuum. The residue was purified by silica gelchromatography (diethyl ethenethyl acetate=10:l to 4:1) to give ethyl 2- (benzylamino)propanoate (34.0 g, 163 mmol, 98.4 % yield, 99.4 % purity) a colorless oil.

[0489] Step B: ethyl 4-rbenzyl-(2-ethoxy-l-methyl-2-oxo-ethyl)amino]butanoate: To a solution of ethyl 2-(benzylamino)propanoate (31.0 g, 150 mmol, 1.00 eq) and ethyl 4-bromobutanoate (87.5 g, 449 mmol, 64.4 mL, 3.00 eq) in MeCN (600 mL) and water (60.0 mL) was added CS2CO3 (97.5 g, 299.12 mmol, 2.00 eq) and KI (4.97 g, 29.9 mmol, 0.20 eq). The reaction mixture was stirred at 80-90 °C for 40 hours. The reaction mixture was filtered and the filter cake was washed with DCM (2 x 100 mL). The filtrate was concentrated under vacuum. The residue was dissolved in DCM (300 mL) and washed with brine (80 mL), dried over Na2S04and concentrated under vacuum. The residue was purified by flash silica gel chromatography (diethyl ether:ethyl acetate = 1 :0 to 20:1) to give ethyl 4-[benzyl-(2-ethoxy-l-methyl-2-oxo- ethyl)amino]butanoate (28.0 g, 87.1 mmol, 58.3 % yield) as a yellow oil.

[0490] Step C: ethyl 1 -benzyl-2-methyl-3-oxo-piperidine-4-carboxylate: To a solution of ethyl 4-[benzyl-(2-ethoxy-l-methyl-2-oxo-ethyl)amino]butanoate (28.0 g, 87.1 mmol, 1.00 eq) in THF (600 mL) was added tBuOK (19.6 g, 174 mmol, 2.00 eq).The reaction mixture was stirred at 18 °C for 1 hour. The reaction mixture was quenched with water (100 mL) and extracted with MTBE (3 x 300mL) and DCM (2 x 200 mL). The combined organic layers were washed with brine, dried over Na2S04and concentrated under vacuum. The crude product was purified by silica gel chromatography (diethyl ether:ethyl acetate=l00:l to 20:1) to give ethyl l-benzyl-2- methyl-3-oxo-piperidine-4-carboxylate (20.0 g, 58.8 mmol, 67.5 % yield, 81.0 % purity) as a yellow oil. ESI MS m / z 276.0 [M+H]+.

[0491] Step D: 7-benzyl-8-methyl-6.8-dihvdro-5H-pyrido[3.4-d]pyrimidine-2,4-dioI: To EtOH (400 mL) was added Na (3.76 g, 163 mmol, 3.88 mL, 2.50 eq). The reaction mixture was stirred at 20 °C for 0.5 hour. To the mixture was added ethyl l-benzyl-2-methyl-3-oxo-piperidine-4- carboxylate (18.0 g, 65.4 mmol, 1.00 eq) and UREA (9.82 g, 163 mmol, 8.77 mL, 2.50 eq) and the reaction mixture was stirred at 80 °C for 80 hours. The solvent was removed under vacuum. The residue was dissolved in water (100 mL) and washed with MTBE (3 x 50 mL). The aqueous phase was adjusted to pH 6-7 with HC1 (15 mL, 12 M). The mixture was filtered and the filter cake was washed with water (30 mL) and dried in vacuum to give 7-benzyl-8-methyl-6,8-dihydiO-5H-pyrido[3,4-d]pyrimidine-2,4 diol (12.0 g, 44.2 mmol, 67.7 % yield, 100 % purity) was obtained as a brown solid. ESI MS m / z 272.0 [M+H]+.

[0492] Step E: benzyl-2,4-dichloiO-8-methyl-6,8-dihvdro-5H-pyrido[3,4-d]pyrimidine: A mixture of 7-benzyl-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (5.00 g, 18.4 mmol, 1.00 eq) in POCI3 (305 g, 1.99 mol, 185 mL, 108 eq) was heated to 1 10 °C for 12 hours. The solvent was removed under vacuum. The residue was dissolved in DCM (500 mL) and poured into saturated Na! ICCh (200 mL) while keeping the pH greater than 7. The organic layer was washed with brine (50 mL), dried over Na2S04.The solution was filtered through a pad of silica gel and the filter cake was washed with DCM (3 x 400 mL). The combined organic layers were concentrated under vacuum to give 7 -benzyl-2, 4-dichloro-8-methyl-6,8-dihydro-5H- pyrido[3,4-d]pyrimidine (4.50 g, 14.6 mmol, 79.2 % yield) as a brown oil.

[0493] Step F: 4-(7-benzyl-2-chloro-8-methyl-6,8-dihvdro-5H-pyrido[3,4-d1pyrimidin-4- yl)piperazine-l -carboxylate: To a solution of 7-benzyl-2,4-dichloro-8-methyl-6,8-dihydro-5H- pyrido[3,4-d]pyrimidine (3.00 g, 9.73 mmol, 1.00 eq) and DIEA (2.52 g, 19.5 mmol, 3.40 mL, 2.00 eq) in dioxane (60.0 mL) was added tert-butyl piperazine- 1 -carboxylate (1.90 g, 10.2 mmol, 1.05 eq). The reaction mixture was stirred at 60 °C for 12 hours. The solvent was removed under vacuum. The residue was purified by silica gel chromatography (diethyl etherrethyl acetate = 2: 1) to give tert-butyl 4-(7-benzyl-2-chloro-8-methyl-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl)piperazine-l-carboxylate (3.30 g, 7.15 mmol, 73.5 % yield, 99.3 % purity) as a yellow solid. ESI MS m / z 458.1 [M+H]+.

[0494] Step G: tert-butyl-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a solution of 2- (dimethylamino)ethanol (583 mg, 6.54 mmol, 655 pL, 3.00 eq) in toluene (20.0 mL) was added Pd(OAc)2(48.9 mg, 218 pmol, 0.10 eq), tert-butyl-4-(7-benzyl-2-chloro-8-methyl-6,8-dihydro- 5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-l -carboxylate (1.00 g, 2.18 mmol, 1.00 eq), Cs2C03(2.13 g, 6.54 mmol, 3.00 eq) and BINAP (272 mg, 436 pmol, 0.20 eq). The reaction mixture was stirred at 1 10 °C for 3 hours under N2. The reaction mixture was concentrated under vacuum. The residue was dissolved in water (10 mL) and extracted with DCM (3c40 mL). The combined organic layers were washed with brine, dried over Na SCL and concentrated under vacuum. The residue was purified by silica gel chromatography (diethyl ether:ethyl acetate =5:1 to 2:1 then DCM:MeOH = 50: 1 to 5:1) to give tert-butyl-4-[7-benzyl-2-[2- (dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l- carboxylate (900 mg, 1.76 mmol, 80.8 % yield) as a brown solid. ESI MS m / z 511.2 [M+H]+.

[0495] Step H: tert-butyl 4-[2-[2-(dimethylamino)ethoxy]-8-methyl-5, 6,7,8- tetrahydropyrido [ 3 ,4-d]pyrimidin-4-yl]piperazine- 1 -carboxylate :To a solution of tert-butyl 4- [7-benzyl-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- yl]piperazine-l -carboxylate (800 mg, 1.57 mmol, 1.00 eq) in MeOH (20.0 mL) was added Pd / C (100 mg) under N2. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (50 psi) at 40°C for 12 hours. The reaction mixture was filtered and the filter cake was washed with MeOH (3 x 200 mL).The filtrate was concentrated under vacuum to give tert-butyl 4-[2-[2-(dimethylamino)ethoxy]-8- methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (450 mg, 1.07 mmol, 68.2 % yield) as brown oil which was used for next step without further purification. ESI MS m / z 421.3 [M+H]+.

[0496] Step I: tert-butyl 4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)ethoxy]-8-methyl- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a mixture of tert- butyl 4-[2-[2-(dimethylamino)ethoxy]-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4- yl]piperazine-l -carboxylate (380 mg, 904 pmol, 1.00 eq) and 3-benzyloxy-l-bromo- naphthalene (31 1 mg, 994 pmol, 1.10 eq) in dioxane (8.00 mL), CS2CO3 (883 mg, 2.71 mmol, 3.00 eq) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (84.3 mg, 181 pmol, 0.20 eq) and Pd2(dba)3(82.7 mg, 90.4 pmol, 0.10 eq) were added. The reaction mixture was stirred at 90 °C for 12 h under N2. The reaction mixture was concentrated under vacuum. The residue was partitioned between DCM (50 mL) and water (20 mL). The reaction mixture was extracted with DCM (50 mL). The combined organic layers were washed with brine (10 mL), dried over Na2S04 and concentrated under vacuum. The residue was purified by silica gel chromatography (diethyl ethenethyl acetate = 5:1 then DCM:MeOH =100:1 to 5:1), followed by purification of the isolated product by preparative TLC (DCM: MeOH=10: l) to give tert- butyl 4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H- pyrido [3 ,4-d]pyrimidin-4-yl]piperazine-l -carboxylate (200 mg, 306 pmol, 33.9 % yield) as brown solid. ESI MS m / z 653.4 [M+H]+.

[0497] Step J: 4- [2- [ 2-( di methyl am i nojethoxy 1 -8 -meth v 1 -4-pi perazi n- 1 -yl-6, 8 -dihydro-5H- pyrido[3,4-dlpyrimidin-7-vHnaphthalen-2-oI bis-trifluoroacetate:To a solution of tert-butyl 4- [2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-8-methyl-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]piperazine-l-carboxylate (100 mg, 177 pmol, 1.00 eq) in DCM (130.00 pL) was added TFA (202 mg, 1.78 mmol, 132 pL, 10.00 eq). The reaction mixture was stirred at 20 °C for 1 hour. The solvent was removed under vacuum to provide 4-[2-[2- (dimethylamino)ethoxy]-8-methyl-4-piperazin-l-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7- yl]naphthalen-2-ol bis-trifluoroacetate (175.00 mg) as a brown oil which was used in the next step without further purification.

[0498] Step K: l-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-8-methyl-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one: To a solution of 4-[2- [2-(dimethylamino)ethoxy]-8-methyl-4-piperazin-l -yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol bis-trifluoroacetate (97.4 mg, 141 pmol, 1.00 eq) in DCM (500.00 pL) was added DIEA (222 mg, 1.72 mmol, 300 pL, 12.2 eq) and prop-2-enoyl prop-2-enoate (14.2 mg, 113 pmol, 0.80 eq) at -40 °C. The reaction mixture was stirred at -40 °C for 0.5 h. The reaction mixture was quenched with a drop of MeOH and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOEI =10: 1) and then by preparative HPLC (column: Phenomenex Synergi C18 150*25*, 10 p; mobile phase: [water (0.1 %TFA)-ACN]; B%: 15%-45%, 13 min) to give l -[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l -naphthyl)-8-methyl-6,8-dihydiO-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one (10.7 mg, 20.7 pmol, three steps 6.8 % yield) as a brown oil. ESI MS m / z 517.2 [M+H]+.EXAMPLE 48l-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-l-yl)-6-methyl-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-l-yl)prop-2-en-l-one trifluoroacetate

[0499] Step A: ethyl 4-[benzyl-(2-ethoxy-2-oxo-ethyl')amino]pentanoate: A solution of ethyl 4- oxopentanoate (47.0 g, 326 mmol, 46.5 mL, 1.50 eq ), ethyl 2-(benzylamino)acetate (42.0 g, 217.3 mmol, 1.00 eq) and AcOH (13.0 g, 217 mmol, 12.4 mL, 1.00 eq) in DCM (800 mL) was stirred at 12-18 °C for 30 min, then cooled at 0-5 °C, NaBH(OAc)3(138 g, 652 mmol, 3.00 eq) was added portion- wise. The mixture was warmed to 10-18 °C and stirred for 16 hours. The reaction mixture was quenched with water (1000 mL) and extracted with DCM (2 x 500 mL). The combined organic phases were dried and concentrated to dryness. The residue was purified by silica gel column eluting with diethyl ether / ethyl acetate (60:1 to 40:1) to provide ethyl 4- [benzyl-(2-ethoxy-2-oxo-ethyl)amino]pentanoate (42.0 g, 91.5 mmol, 42.1 % yield, 70 % purity) as colorless oil. ESI MS m / z 322.2 [M+H]+.

[0500] Step B: ethyl 1 -benzyl-2-methyl-5-oxo-piperidine-4-carboxylate: A solution of ethyl 4- [benzyl-(2-ethoxy-2-oxo-ethyl)amino]pentanoate (37.00 g, 115.12 mmol, 1.00 eq) and t-BuOK (16.8 g, 150 mmol, 1.30 eq) in toluene (30.0 mL) was stirred at 25 °C for 5 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were dried and concentrated to dryness to provide ethyl l-benzyl-2-methyl-5- oxo-piperidine-4-carboxylate (14.6 g, 53.0 mmol, 46 % yield) as yellow oil which was used directly in the next step.

[0501] Step C: 7-benzyl-6-methyl-6,8-dihvdro- pyrido[3,4-d]pyrimidine-2,4-diol: Na (3.05 g,133 mmol, 3.14 mL, 2.50 eq) was dissolved in EtOH (280 mL), and then ethyl l-benzyl-2- methyl-5-oxo-piperidine-4-carboxylate (14.6 g, 53.0 mmol, 1.00 eq) and urea (7.96 g, 133 mmol, 7.11 mL, 2.50 eq) were added. The reaction mixture was heated to reflux (78 °C) for 16 hrs under N2. The reaction mixture was concentrated to dryness. The residue was dissolved in water (100 mL), washed with MTBE (100 mL). The pH of the water phase was adjusted to pLI 6-7 with 6N HC1 (2 mL). The resulting solid was collected by filtration and dried under vacuum at 60 °C to provide 7-benzyl-6-methyl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidine-2,4-diol (5.00 g, 17.1 mmol, 32.3 % yield, 93 % purity) as light yellow solid.

[0502] Step D: 7-benzyl-2,4-dichloiO-6-methyl-6,8-dihydro-5 / 7-pyrido[3,4-d]pyrimidine: POCb (49.5 g, 323 mmol, 30.0 mL, 58.4 eq) and 7-benzyl-6-methyl-6,8-dihydro-57 / -pyrido[3,4- d]pyrimidine-2,4-diol (1.50 g, 5.53 mmol, 1.00 eq) were heated to 100 °C under reflux for 12 hours. The reaction was concentrated to dryness to remove POCI3. The residue was dissolved in DCM (40 mL) and washed with saturated NaHC03aqueous / saturated aqueous Na2C03(1 / 1, 60 mL). The mixture was filtered and the organic layers were dried over Na2S04, filtered and concentrated under vacuum to give 7-benzyl-2,4-dichloro-6-methyl-6,8-dihydro-57 / -pyrido[3,4- djpyrimidine (2.08 g, crude) as a brown solid which was used directly in the next step without further purification. ESI MS m / z 307.9, 309.9 [M+H]+.

[0503] Step E: 4-(7-benzyl-2-chloro-6-methyl-6,8-dihvdro- pyrido[3,4-d]pyrimidin-4-vDpiperazine- 1 -carboxylate :To a mixture of 7-benzyl-2,4-dichloro-6-methyl-6,8-dihydro-5 / / - pyrido[3,4-d]pyrimidine (2.50 g, 8.11 mmol, 1.00 eq) and ieri-butyl piperazine- 1 -carboxylate (1.54 g, 8.27 mmol, 1.02 eq) in dioxane (50.0 mL) was added DIEA (3.14 g, 24.3 mmol, 4.25 mL, 3.00 eq). The mixture was stirred at 60 °C for 20 hours. The mixture was concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with DCM (2 x 80 mL). The organic layers were dried over Na2S04and concentrated under vacuum. The residue was purified by automated flash chromatography system (diethyl ether / ethyl acetate 50:1 to 2:1) to give tert-buty\ 4-(7-benzyl-2-chloro-6-methyl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-4- yl)piperazine-l -carboxylate (2.59 g, 5.29 mmol, 65.2 % yield, 93.5 % purity) as a yellow solid.

[0504] Step F: / er / -butyl 4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5 / / - pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a solution of 2- (dimethylamino)ethanol (701 mg, 7.86 mmol, 788 pL, 3.00 eq) in THF (45.0 mL) was added NaH (210 mg, 5.24 mmol, 60.0 % purity, 2.00 eq) at 15 °C under N2. After stirring at 15 °C for 0.5 hour, tert-bxxtyl 4-(7-benzyl-2-chloro-6-methyl-6,8-dihydiO-57 / -pyrido[3,4-d]pyrimidin-4- yl)piperazine-l -carboxylate (1.20 g, 2.62 mmol, 1.00 eq) was added. The mixture was stirred at 1 10 °C for 18 hours in a sealed tube. The mixture was concentrated under vacuum. The residue was purified by column chromatography over A1203(DCM / MeOFl 100:1 to 10:1) to give tert- butyl 4- [7-benzyl-2- [2-(dimethylamino)ethoxy] -6-methyl-6, 8-dihydro-5 / 7-pyrido [3 ,4- d]pyrimidin-4-yl]piperazine-l -carboxylate (1.38 g, 2.36 mmol, 90.3 % yield, 87.5% purity) as a yellow oil. ESI MS m / z 51 1.3 [M+FI]+.

[0505] Step G: fer / -butyl 4T2T2-(dimethylamino)ethoxy]-6-methyl-5,6,7,8- tetrahvdropyridoi3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a solution of tert- butyl 4- [7-benzyl-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-4- yl]piperazine-l-carboxylate (1.50 g, 2.94 mmol, 1.00 eq ) in MeOH (80.0 mL) was added Pd / C (450 mg) under N2. The suspension was degassed under vacuum and purged with hydrogen 4 times. The mixture was stirred under hydrogen (50 psi) at 40 °C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (DCM / MeOH 40 / 1 to 10 / 1) to give tert- butyl 4-[2-[2-(dimethylamino)ethoxy]- 6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (1.15 g, 2.46 mmol, 83.7 % yield, 90.0 % purity) as a yellow oil.

[0506] Step H: tert- butyl 4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)ethoxy]-6- methyl-6,8-dihydro-577-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: Pd2(dba)3(109 mg, 1 19 pm ol, 0.10 eq) was added to a solution of tert- butyl 4-[2-[2-(dimethylamino)ethoxy]-6- methyl-5,6,7,8-tetrahydiOpyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (500 mg, 1.19 mmol, 1.00 eq), 3-benzyloxy-l-bromo-naphthalene (410 mg, 1.31 mmol, 1.10 eq), 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (11 1 mg, 238 pmol, 0.20 eq) and Cs2C03(1.16 g, 3.57 mmol, 3.00 eq) in dioxane (10.0 mL). The reaction mixture was stirred at 90 °C for 12 hours under N2. The mixture was concentrated under vacuum. The residue was diluted with water (5 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by column chromatography over AI2O3 (DCM / MeOH 100 / 1 to 30 / 1) and by preparative TLC (DCM / MeOH 5:1) to give er / -butyl 4-[7-(3-benzyloxy-l-naphthyl)-2-[2- (dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-4-yl]piperazine-l- carboxylate (309 mg, 453 pmol, 38.1 % yield, 95.8 % purity) as a yellow oil.

[0507] Step I: / <?r / -butyl 4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-6-methyl- 6,8-dihydro-57 / -pyrido[3,4-d]pyrimidin-4-yl]piperazine-l -carboxylate: To a solution of tert- butyl 4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5 / 7- pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (340 mg, 521 pmol, 1.00 eq) in MeOLI (6.80 mL) was added Pd / C (120 mg) under N2. The suspension was degassed under vacuum and purged with hydrogen 4 times. The mixture was stirred under hydrogen (15 psi) at 40 °C for 1.5hours. The mixture was concentrated under vacuum to give tert- butyl 4-[2-[2- (dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-6-methyl-6,8-dihydro-5 / / -pyrido[3,4- d]pyrimidin-4-yl]piperazine-l-carboxylate (210 mg, 312 pmol, 59.8 % yield, 83.5 % purity) as a pink solid which was used directly in the next step without further purification. ESI MS m / z 563.3 [M+H]+.

[0508] Step J: 4-[2-[2-(dimethylamino)ethoxy]-6-methyl-4-piperazin-l-yl-6,8-dihydro-5 / / - pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol trifluoroacetate : To a solution of te / 7-butyl 4-[2- [2-(dimethylamino)ethoxy |-7-(3 -hydroxy- 1 -naphthyl)-6-methy 1-6, 8-di hydro-5 / / -pyrido[3, 4- d]pyrimidin-4-yl]piperazine-l-carboxylate (180 mg, 320 pmol, 1.00 eq) in DCM (240 pL) was added TFA (365 mg, 3.20 mmol, 237 pL, 10.0 eq). The mixture was stirred at 18 °C for 0.5 hour. The mixture was concentrated under vacuum to give 4-[2-[2-(dimethylamino)ethoxy]-6- methyl-4-piperazin-l-yl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol trifluoroacetate (273 mg) as a yellow oil which was used directly in the next step without further purification.Step K: l-[4-[2-[2-(dimethylarnino)ethoxy]-7-(3-hydroxy-l-naphthyl)-6-methyl-6, 8-dihydro- 5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one: To a solution of 4-[2-[2- (dimethylamino)ethoxy]-6-methyl-4-piperazin-l-yl-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-7- yl]naphthalen-2-ol trifluoroacetate (148 mg, 320 pmol, 1.00 eq) and DIEA (494 mg, 3.83 mmol, 668 pL, 12.0 eq) in DCM (500 pL) was added prop-2-enoyl prop-2-enoate (32.3 mg, 256 pmol, 0.80 eq) dropwise at - 50 °C. The mixture was stirred at -40 to -20 °C for 30 minutes. The reaction was quenched with MeOH (20.5 mg) and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Synergi Cl 8 150*25*, 10 p; mobile phase: [water (0.1% TFA)-ACN]; B%: 8%-38%,13 min) to give l-[4-[2-[2- (dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-6-methyl-6,8-dihydro-5FI-pyrido[3,4- d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one trifluoroacetate (73.7 mg, 1 13 pmol, 35.2 % yield, 96.3 % purity) as a yellow solid. ESI MS m / z 517.3 [M+FI]+.EXAMPLE 49l-(4-(2-(2-(3-fluoropyrrolidin-l-yl)ethoxy)-7-(3-hydroxynaphthalen-l-yl)-5, 6,7,8- tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one

[0509] Step A: tert- butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2-[2-(3-fluoropyrrolidin-l- yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate :A mixture of 2-(3- fluoropyrrolidin-l-yl)ethanol (401 mg, 3.01 mmol, 1.60 eq), er / -butyl 4-(4- benzyloxycarbonylpiperazin-l-yl)-2-methylsulfonyl- 6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidine- 7-carboxylate (1.00 g, 1.88 mmol, 1.00 eq), Cs2C03(1.84 g, 5.64 mmol, 3.00 eq), Pd(OAc)2(42.2 mg, 188 pmol, 0.10 eq) and BINAP (234 mg, 376 pmol, 0.20 eq) in toluene (50.00 mL) was stirred at 1 10 °C for 3 hours. The mixture was concentrated under vacuum. The residue was purified by column chromatography over silica gel (petroleum ether / ethyl acetate 10:1 to 100:1). The desired fractions were collected and concentrated under vacuum to give tert- butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2-[2-(3-fluoiOpynOlidin-l-yl)ethoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidine-7-carboxylate (1.20 g, 1.07 mmol, 56.8 % yield, 52 % purity) as a yellow solid. ESI MS m / z 585.3 [M+H]+.

[0510] Step B: benzyl 4-r2-[2-(3-fluoropyrrolidin-l-yl)ethoxy]-5,6,7,8-tetrahydropyrido [3,4- d]pyrimidin-4-yl]piperazine-l-carboxylate: To a solution of tert- butyl 4-(4- benzyloxycarbonylpiperazin-1- yl)-2-[2-(3-fluoropyrrolidin-l-yl)ethoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidine-7-carboxylate (1.20 g, 2.05 mmol, 1.00 eq) in DCM (10.00 mL) was added TFA (3.51 g, 30.8 mmol, 2.28 mL, 15.00 eq) at 0 °C. The mixture was warmed to 25 °C and stirred for 16 hours. The mixture was diluted with water (100 mL) and the solution was extracted with ethyl acetate (2 x 100 mL). The water layer was basified with saturated aqueous sodium carbonate solution (50 mL) and then extracted with ethyl acetate (2 x 100 mL). Thecombined organic layers were washed with brine (1 x 100 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to provide benzyl 4-[2-[2-(3- fluoropyrrolidin-l -yl)ethoxy]-5,6,7,8-tetrahydropyrido [3,4-d]pyrimidin-4-yl]piperazine-l- carboxylate (800 mg, 1.65 mmol, 80.4 % yield) as a yellow gum. ESI MS m / z 485.3 [M+fI]+.

[0511] Step C: benzyl 4-[2-[2-(3 fluoropyrrolidin-l-y!)cthoxy]-7-(3-methoxy-l-naphthyl)-6,8- dihydro-5i / -pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: A mixture of benzyl 4-[2-[2- (3-fluoropyrrolidin-l-yl)ethoxy]- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l- carboxylate (750 mg, 1.55 mmol, 1.00 eq), (3 -methoxy-1 -naphthyl) trifluoromethanesulfonate (949 mg, 3.10 mmol, 2.00 eq), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (144.66 mg, 310.00 pmol, 0.20 eq), Pd2(dba)3(141.94 mg, 155.00 pmol, 0.10 eq) and CS2CO3 (1.52 g, 4.65 mmol, 3.00 eq) in toluene (70.00 mL) was stirred at 1 10 °C for 16 hours. The mixture was concentrated under vacuum and then diluted with ethyl acetate (100 mL) and water (100 mL). The separated organic layer was washed with brine (1 x 100 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by columnchromatography over silica gel (petroleum ether / ethyl acetate 10: 1 to ethyl acetate / methanol 10: 1). The desired fractions were collected and concentrated under vacuum to give benzyl 4-[2- [2-(3-fluoropyrrolidin-l -yl)ethoxy]-7-(3-methoxy-l-naphthyl)-6,8-dihydro-5 / / -pyrido[3,4- d]pyrimidin-4-yl]piperazine-l -carboxylate (700 mg, 961 pmol, 62.0 % yield, 88% purity) as a brown solid. ESI MS m / z 641.3 [M+H]+.

[0512] Step D: 2- G2-(3 -fluoropyrrolidin- -7-(3 -methoxy- 1 -naphthylV4-piperazin- 1 -yl-6,8-dihvdro-5H-pyridor3.4-d]pyrimidine: A mixture of benzyl 4-[2-[2-(3-fluoropyrrolidin-l- yl)ethoxy]-7- (3-methoxy-l -naphthyl)-6,8-dihydro-5 / / -pyrido[3,4-d]pyrimidin-4-yl]piperazine- 1-carboxylate (700.00 mg, 1.09 mmol, 1.00 eq) in MeOH was hydrogenated (15 psi) at 40 °C with dry Pd / C (140 mg,) as a catalyst for 4 hours. The catalyst was filtered through a Celite® pelt and the filtrate was concentrated under vacuum to provide 2-[2-(3-fluoiOpyrrolidin-l - yl)ethoxy] -7-(3 -methoxy- 1 -naphthyl)-4-piperazin- 1 -yl-6,8-dihydro-5H-pyrido [3 ,4-d]pyrimidine (500 mg, 987 pmol, 90.6 % yield) as a brown solid.

[0513] Step E: l-[4-[2-[2-(3-fluoropyrrolidin-l -yl)ethoxy]-7-(3-methoxy-l-naphthyl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l -yl]prop-2-en-l -one: To a mixture of 2-[2- (3-fluoropyrrolidin-l -yl)ethoxy]-7- (3-methoxy-l -naphthyl)-4-piperazin-l -yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (500 mg, 987 pmol, 1.00 eq) and DIEA (255 mg, 1.97 mmol, 345 pL, 2.00 eq) in dichloromethane (8 mL) was added a solution of prop-2-enoyl prop-2-enoate (124 mg, 987 pmol, 1.00 eq) in dichloromethane (2 mL) at - 40 °C under nitrogen atmosphere. The mixture was warmed to 25 °C and stirred for 1 hour. The mixture was diluted with water (20 mL) and dichloromethane (30 mL). The separated organic layer was washed with brine (1 x 30 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by colum...

Claims

CLAIMSWE CLAIM:

1. A compound of formula (II):Formula (II) or a pharmaceutically acceptable salt thereof: wherein:X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R8;Y is a bond, 0, S or NR5;R1is MF(0)C(Ra) = C(RB)Por -S02C(RA) = C(RB)P;R2is hydrogen, alkyl, hydroxyalkyl, dihydroxy alkyl, alkylaminylalkyl. dialkylaminylalkyl, -Z- NR3R10, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R9; each Z is Cl - C4 alkylene; each R3is independently Cl - C3 alkyl, oxo, haloalkyl, hydroxyl or halogen; L is a bond, -C(O)-, or Cl - C3 alkylene;R4is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R6, R7or R8; each R5is independently hydrogen or Cl - C3 alkyl;R6is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R7; each R7is independently halogen, hydroxyl, Cl - C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is 0 or S;R8is oxo, Cl - C3 alkyl, C2 - C4 alkynyl, heteroalkyl, cyano, -C(0)0R5, -C(0)N(R5)2, -N(R5)2, wherein the Cl - C3 alkyl may be optionally substituted with cyano, halogen, -OR5, -N(R5)2, or heteroaryl; each R9is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, Cl - C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the Cl - C6 alkyl may be optionally substituted with cycloalkyl; each R10is independently hydrogen, acyl, Cl - C3 alkyl, heteroalkyl or hydroxyalkyl;R11is haloalkyl;RAis absent, hydrogen, deuterium, cyano, halogen, Cl - C-3 alkyl, haloalkyl, heteroalkyl, - C(0)N(R3)2, or hydroxyalkyl; each RBis independently hydrogen, deuterium, cyano, Cl - C3 alkyl, hydroxyalkyl, heteroalkyl, Cl - C3 alkoxy, halogen, haloalkyl, -ZNRsRn, -C(0)N(R5)2, -NHC(0)C1 - C3 alkyl, - CH2NHC(0)C1 - C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and Cl - C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R7; or when = isadouble bond and p is two, one RBis hydrogen and RAand one RBand the carbon atoms to which they are attached form a 4-8 membered partially saturated cycloalkyl substituted with oxo;m is zero or an integer between 1 and 2; p is one or two; and wherein. when - is a triple bond then RAis absent, p equals one and RBis hydroxyalkyl, or when . is a double bond then RAis present, RBis present and p equals two, wherein when RAis hydrogen or Cl - C3 alkyl, at least one RBis deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, -ZNRsRn, -C(0)N(R5)2, -NHC(0)C1 - C3 alkyl, -CH2NHC(0)C1 - C3 alkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and Cl - C3 alkyl; or when each RBis hydrogen, then RAis deuterium, cyano, halogen, haloalkyl, -C(0)N(R;,)2, hydroxyalkyl or heteroalkyl.

2. The compound of claim 1 , wherein R!-X is:wherein the piperazinyl ring is optionally substituted with R8.

3. The compound of claim 2, wherein R1is C(())C(RA)=C(RB)P.

4. The compound of claim 3, wherein - is a triple bond and RAis absent, p is one andRBis hydroxyalkyl or Cl - C3 alkoxy.

5. The compound of claim 3, wherein - is a double bond and RAis hydrogen, p is two and at least one RBis independently deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, -ZNR5Rn, -C(0)N(R5)2, -NHC(0)C1 - C3 alkyl or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy or Cl - C3 alkyl.

6. The compound of claim 5, wherein the at least one RBis halogen.

7. The compound of claim 5, wherein the at least one RBis haloalkyl.

8. The compound of claim 5, wherein the at least one RBis -ZNR5Rn.

9. The compound of claim 8, wherein Z is methylene, R3is methyl and R1 1istrifluoromethyl.

10. The compound of claim 5, wherein the at least one RBis cyano.

11. The compound of claim 5. wherein the at least one RBis hydroxyalkyl.

12. The compound of claim 5, wherein the at least one RBis heteroalkyl.

13. The compound of claim 12, wherein the heteroalkyl is methoxymethyl.

14. The compound of claim 5, wherein the at least one RBis -C(0)N(R3)2, wherein each R3is hydrogen.

15. The compound of claim 5, wherein the at least one RBis -C(0)N(R5)2, wherein each R3is Cl - C3 alkyl.

16. The compound of claim 5, wherein the at least one RBis heteroaryl optionally substituted with one or more R7.

17. The compound of claim 16, wherein the heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, each substituted with one or more R7.

18. The compound of claim 5, wherein the at least one RBis heteroarylalkyl optionally substituted with one or more R7.

19. The compound of claim 18, wherein the heteroaryl portion of the heteroarylalkyl is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, each optionally substituted with one or more R7.

20. The compound of claim 5, wherein the at least one RBis heterocyclylalkyl substituted with one or more R7.

21. The compound of claim 20, wherein the heterocyclyl portion of the heterocyclylalkyl is azetindinyl, pyrrolidinyl, piperidinyl piperazinyl or morpholinyl, each substituted with one or more groups independently selected from halogen, hydroxyl, alkoxy or Cl - C3 alkyl.

22. The compound according to any of claims 5-21, wherein the double bond is in the E configuration..

23. The compound according to any of claims 5-21, wherein the double bond is in the Z configuration..

24. The compound of claim 5, wherein is a double bond and p is two, each RBis hydrogen, and RAis deuterium, cyano, halogen, haloalkyl, heteroalkyl, -C(0)N(R5)2, or hydroxy alkyl.

25. The compound of claim 24, wherein RAis halogen.

26. The compound of claim 24, wherein RAis haloalkyl.

27. The compound of claim 24. wherein RAis cyano.

28. The compound of claim 24, wherein RAis heteroalkyl.

29. The compound of claim 28, wherein the heteroalkyl is methoxymethyl.

30. The compound of claim 28, wherein the heteroalkyl is alkoxy.

31. The compound of claim 24, wherein RAis -C(0)N(R5)2, wherein each R5is hydrogen.

32. The compound of claim 24, wherein RAis hydroxyalkyl.

33. The compound of claim 2, wherein - is a double bond and p is two, one RBis hydrogen, the second RBis dialkylaminylalkyl, and RAis halogen.

34. The compound of claim 2, wherein - is a double bond and p is two, each RBis deuterium, and RAis deuterium.

35. The compound of claim 2, wherein when = is a double bond and p is two, one RBis hydrogen and RAand one RBand the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl substituted with oxo.

36. The compound of according to any one of claims 2-35, wherein Y is 0.

37. The compound according to any one of claims 2-36, wherein R2is selected from the group consisting of hydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -ZNR5R10,heterocyclyl and heterocyclylalkyl, wherein each of the Z, heterocyclyl or heterocyclylalkyl are independently optionally substituted with R9.

38. The compound of claim 37, wherein R2is heterocyclylalkyl optionally substituted with one or more R9.

39. The compound of claim 38, wherein the heterocyclyl of the heterocyclylalkyl is independently azetidinyl, methylazetidinyl, ethylazetidinyl, isopropylazetidinyl,difluoroazetidinyl, cyclopropylazetidinyl, tertrahydropyranyl azetidinyl, tetrahydropyranyl, pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, isopropylpyrrolidinyl,cycloalkylalkylpyrrolidinyl, hydroxypyrrolindinyl, fluoropyrrolidinyl, difluoropyrrolidinyl, (N- methyl)fluoropyrrolidinyl, (N-methyl)difluoropyrrolidinyl, methoxyethylpyrrolidinyl, (N- methyl)methoxypyrrolidinyl, piperazinyl, dimethylaminylpyrrolidinyl, pyrrolidinone, methylpynolidinone, morpholinyl, methylmorpholinyl, ethylmorpholinyl, isopropylmorpholinyl, oxetanyl, l,4-oxazepanyl, piperdinyl, methylpiperidinyl acylpiperdinyl, cyanopiperdinyl, cycloalky lpiperdinyl, halopiperdinyl, dihalopiperdinyl, lluoropiperdinyl, difluoropiperdinyl, alkoxypiperdinyl, pyrrolidonyl, piperidinonyl, tetrahydropyrrolizinyl, thiomorpholinyl-l,l- dioxide, 3-azabicyclo[3.l .0]hexanyl, oxa-5-azabicyclo[2.2.l]heptan-5-yl, orazabicyclo[2.2.l]heptan-2-yl.

40. The compound of claim 39, wherein the (N-methyl)difluoropyrrolidinyl is 3,3-difluoro-l- methylpyrrolidinyl.

41. The compound of claim 39, wherein the heterocyclyl is N-methylpyrrolidinyl,42. The compound of claim 37, wherein R2is dialkylaminylalkyl optionally substituted with one or more R9.

43. The compound according to any one of claims 2-42, wherein R4is aryl optionally substituted with one or more R7.

44. The compound of claim 43, wherein the aryl is selected from the group consisting of phenyl and naphthyl optionally substituted with one or more R7.

45. The compound of claim 44, wherein the phenyl and the naphthyl are each optionally substituted with one or more R7selected from the group consisting of halogen, hydroxyl, Cl - C6 alkyl, haloalkyl, Q-haloalkyl, and alkoxy.

46. The compound of claim 45, wherein R7is selected from the group consisting of halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl, hydroxyl and cyano.

47. The compound according to any one of claims 2-42, wherein R4is heteroaryl.

48. The compound according to any one of claims 2-42, wherein R4is aralkyl optionally substituted with one or more R7.

49. The compound according to any one of claims 2-48, wherein m is zero.

50. The compound according to any one of claims 2-49, wherein L is a bond.

51. The compound according to any one of claims 2-50, wherein R8is heteroalkyl, C2-C4 alkynyl, or Cl - C3alkyl optionally substituted with -OR5, cyano or heteroaryl.

52. The compound of claim 51 , wherein R8is Cl - C3 alkyl optionally substituted with cyano.

53. The compound of claim 51 , wherein R8is cyanomethyl.

54. The compound according to any one of claims 51-53, wherein X is substituted with one R8.

55. The compound of claim 1, wherein the compound is:1406140756. The compound of claim 1 , wherein the compound is of Formula 1I-A:Formula II- A wherein the piperazinyl ring is optionally substituted with R8, where R1, R3, R4, R3, R8, R10, L and m are as defined in claim 1 and R1 1is hydrogen, methyl or hydroxyalkyl.

57. The compound of claim 56, wherein R1is -C(0)C(RA) - C(RB)Pand - is a double bond and RAis hydrogen, p is two and at least one RBis independently deuterium, cyano.halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl heteroarylalkyl, -ZNR5Rn, - C(0)N(R5)2, -NHC(0)C1 - C3 alkyl or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy or Cl - C3 alkyl.

58. The compound of claim 56, wherein R1is -C(())C(RA) C(RB)Pand . is a double bond, each RBis hydrogen, and RAis deuterium, cyano, halogen, Cl - C-3 alkyl, haloalkyl, heteroalkyl, -C(0)N(R5)2, or hydroxyalkyl.

59. The compound according to any of claims 57-58, wherein R5and R10are each Cl - C3 alkyl.

60. The compound of claim 59, wherein R1 1is methyl.

61. The compound of claim 59, wherein R8is heteroalkyl, C2-C4 alkynyl, or Cl - C3 alkyl optionally substituted with -OR3, cyano or heteroaryl.

62. The compound according to any one of claims 54-61 , wherein L is a bond, and R4is aryl or heteroaryl, each optionally substituted with one or more R6, R7or R8.

63. The compound of claim 62, wherein the aryl or heteroaryl are substituted with one or more R7independently selected from hydroxyl, amino, halogen, Cl - C3 alkyl, haloalkyl, Q- haloalkyl, cycloalkyl and alkoxy.

64. The compound of claim 1 , wherein the compound is of Formula II-B:Formula II-B where the piperazinyl ring is optionally substituted with R8, and R1, R3, R4, R8, L and m are as defined in claim 1.

65. The compound of claim 64, wherein R1is -C(0)C(RA) — C(RB)Pand is a double bond and RAis hydrogen, p is two and at least one RBis independently deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, -ZNR\U, - C(0)N(R5)2, -NHC(0)C1 - C3 alkyl or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and Cl - C3 alkyl.

66. The compound of claim 64, wherein R1is -C(0)C(RA) . C(RB)Pand . is a double bond, each RBis hydrogen, and RAis deuterium, cyano, halogen, Cl - C-3 alkyl, haloalkyl, heteroalkyl, -C(0)N(R5)2, or hydroxyalkyl.

67. The compound according to any one of claims 65-66, wherein R2is heterocyclylalkyl optionally substituted with one or more R9.

68. The compound of claim 67, wherein the heterocyclyl portion of the heterocyclylalkyl is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1 ,4-oxazepanyl, thiomorpholinyl- 1,1 -dioxide, 3-azabicyclo[3.l.0]hexanyl, 2-oxa-5-azabicyclo[2.

2. l]heptan-5-yl, or azabicyclo [2.2.1 ]heptan-2- yl, each optionally substituted with one or more R9.

69. The compound of claim 68, wherein each R9is independently acyl, oxo, halogen, cyano, Cl - C6 alkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, aralkyl or dialkylamidoalkyl.

70. The compound of claim 69, wherein each R9is independently C1-C6 alkyl, heteroalkyl, or halogen.

71. The compound according to any one of claims 65-70, wherein the heterocyclyl is pyrrolidinyl optionally substituted with one or more R9.

72. The compound of claim 71 , wherein the heterocyclyl is 3,3-difluoro-l- methylpyrrolidinyl.

73. The compound of claim 72, wherein R8is heteroalkyl, C2-C4 alkynyl, or Cl - C3alkyl optionally substituted with -OR5, cyano or heteroaryl.

74. The compound of claim 73, wherein R8is C 1-C3 alkyl optionally substituted with cyano.

75. The compound according to any one of claims 65-74, wherein L is a bond and R4is aryl or heteroaryl, each optionally substituted with one or more R6, R7or R8.

76. The compound of claim 75, wherein the aryl or heteroaryl are substituted with one or more R7independently selected from hydroxyl, amino, halogen, Cl - C3 alkyl, haloalkyl, Q- haloalkyl, cycloalkyl and alkoxy.

77. The compound according to any one of claims 75-76, wherein R4is aryl optionally substituted with one or more R6or R7.

78. The compound according to claim 77, wherein R4is phenyl or naphthyl, each optionally substituted with one or more R6or R7.

79. The compound according to claim 77, wherein R4is optionally substituted with one or more R7independently selected from halogen, C1-C6 alkyl, and haloalkyl.

80. The compound according to any one of claims 65-79, wherein m is zero.

81. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula (II), Formula II-A or Formula II-B according to any one of claims 1-80, and a pharmaceutically acceptable excipient.

82. A method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula (II), Formula II-A or Formula II-B according to any one of claims 1-80,pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound of Formula (II), Formula II-A or Formula II-B, or pharmaceutically acceptable salt thereof.

83. A method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of Formula (II), Formula II-A or Formula II-B, or a pharmaceutically acceptable salt thereof according to any one of claims 1 -80, alone or combined with a pharmaceutically acceptable carrier, excipient or diluents.

84. The method of claim 83, wherein the therapeutically effective amount of the compound is between about 0.01 to 100 mg / kg per day.

85. The method of claim 84, wherein the therapeutically effective amount of the compound is between about 0.1 to 50 mg / kg per day.

86. The method of claim 83, wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma,retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamouscell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin:malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

87. The method of claim 86, wherein the cancer wherein the cancer is a KRas G12C- associated cancer.

88. The method of claims 83-87, wherein the cancer is non-small cell lung cancer.

89. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C- associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (II), Formula II-A or Formula II-B or a pharmaceutically acceptable salt thereof according to any one of claims 1-80, or a pharmaceutical composition thereof.

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